JP4225779B2 - Amide derivatives as NMDA receptor antagonists - Google Patents
Amide derivatives as NMDA receptor antagonists Download PDFInfo
- Publication number
- JP4225779B2 JP4225779B2 JP2002537711A JP2002537711A JP4225779B2 JP 4225779 B2 JP4225779 B2 JP 4225779B2 JP 2002537711 A JP2002537711 A JP 2002537711A JP 2002537711 A JP2002537711 A JP 2002537711A JP 4225779 B2 JP4225779 B2 JP 4225779B2
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- Prior art keywords
- hydroxy
- methanone
- indol
- formula
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229940127523 NMDA Receptor Antagonists Drugs 0.000 title description 3
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- -1 hydroxy-diphenylmethyl Chemical group 0.000 claims description 66
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- 150000003839 salts Chemical class 0.000 claims description 28
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
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- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- OSXYEGVWXKWYRA-UHFFFAOYSA-N (6-hydroxy-1h-benzimidazol-2-yl)-[4-[(4-methylphenyl)methyl]piperidin-1-yl]methanone Chemical compound C1=CC(C)=CC=C1CC1CCN(C(=O)C=2NC3=CC(O)=CC=C3N=2)CC1 OSXYEGVWXKWYRA-UHFFFAOYSA-N 0.000 claims description 3
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- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 claims 13
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Classifications
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Description
【0001】
本発明は、 式(I):
【化9】
R1、R2、R3およびR4のうちの1つは、−OHまたは−NH2基であり、他は水素原子であるか、または、
【0002】
隣接する2つのR1、R2、R3およびR4基は、所与の場合、1つまたはそれ以上の同一または異なる追加のヘテロ原子および−CH=および/または−CH2−基とともに、5−6員のホモ−またはヘテロ環、好ましくは、ピロール、ピラゾール、イミダゾール、オキサゾール、オキソ−オキサゾリジン、または3−オキソ−1,4−オキサジン環を形成し、R1、R2、R3およびR4基の他の2つは、水素原子であり、
【0003】
R5およびR6は、それらの間の窒素原子とともに、飽和または不飽和の4−6員のヘテロ環を形成し、上記ヘテロ環はヒドロキシ基、および/または、所与の場合、フェニルまたはフェノキシ、フェニル−(Cl−C4アルキル)、フェニル−(Cl−C4アルコキシ)、フェノキシ−(Cl−C4アルキル)、アニリノ、フェニル−(Cl−C4アルキルアミノ)、[フェニル−(Cl−C4アルキル)]−アミノ、ベンゾイル、ヒドロキシ−ジフェニルメチル、Cl−C4アルコキシカルボニル−フェノキシメチルまたはベンズヒドリデン基(ここで、芳香族環は、所望により、1またはそれ以上のハロゲン原子、シアノまたはヒドロキシ基、Cl−C4アルキルまたはCl−C4アルコキシ基で置換されていてもよい)で置換されており、
【0004】
XおよびYの意味は、独立して酸素または窒素原子、または−CH=である]
で示される、NMDA受容体拮抗カルボン酸アミド誘導体、および酸および塩基によって形成されるそれらの塩に関する。
【0005】
本発明はまた、酸もしくは塩基によって形成される式(I)で示される化合物の塩、具体的には、医薬的に許容され得る酸または塩基によって形成される塩に関するものであり、式(I)で示される化合物の意味は、特に断らなければ、遊離の化合物または塩のいずれかである。
【0006】
本発明の特に重要な化合物の群は、式(Ia):
【化10】
[式中、R1、R2、R3、R4、R5およびR6の意味は式(I)の化合物についての記載と同じである]で示される化合物である。
【0007】
式(I)で示される特に重要なカルボン酸アミド誘導体は下記のものである:
1−(4−ベンジルオキシピペリジン−1−イル)−1−(6−ヒドロキシ−1H−インドール−2−イル)メタノン、
1−(4−ベンジルピペリジン−1−イル)−1−(4−ヒドロキシ−1H−インドール−2−イル)メタノン、
1−(4−ベンジルピペリジン−1−イル)−1−(6−ヒドロキシ−1H−インドール−2−イル)メタノン、
1−(4−ベンジルピペリジン−1−イル)−1−(5−ヒドロキシ−1H−インドール−2−イル)メタノン、
1−(6−ヒドロキシ−1H−インドール−2−イル)−1−[4−(4−メチルベンジルオキシ)ピペリジン−1−イル)]メタノン、
1−(6−ヒドロキシ−1H−インドール−2−イル)−1−(4−フェノキシメチルピペリジン−1−イル)メタノン、
1−(6−ヒドロキシ−1H−インドール−2−イル)−1−[4−(4−メチルベンジル)−4−ヒドロキシピペリジン−1−イル)]メタノン、
1−[4−(4−フルオロベンジルピペリジン−1−イル)]−1−(6−ヒドロキシ−1H−インドール−2−イル)メタノン、
1−(6−ヒドロキシ−1H−インドール−2−イル)−1−(4−フェノキシピペリジン−1−イル)メタノン、
1−[4−(4−フルオロベンジルピペリジン−1−イル)]−1−(5−ヒドロキシ−1H−インドール−2−イル)メタノン、
1−(4−ヒドロキシ−1H−インドール−2−イル)−1−(4−フェノキシメチルピペリジン−1−イル)メタノン、
1−(6−ヒドロキシ−1H−インドール−2−イル)−1−(4−フェノキシ−3,6−ジヒドロ−2H−ピリジン−1−イル)メタノン、
1−(4−ベンジルオキシピロリジン−1−イル)−1−(6−ヒドロキシ−1H−インドール−2−イル)メタノン、
1−[4−(4−クロロベンジルオキシ)−ピペリジン−1−イル)]−l−(6−ヒドロキシ−1H−インドール−2−イル)メタノン、
(4−ベンジルピペリジン−1−イル)−(6−ヒドロキシ−1H−ベンゾイミダゾール−2−イル)−メタノン、および
(6−ヒドロキシ−1H−ベンゾイミダゾール−2−イル)−[4−(4−メチル−ベンジル)−ピペリジン−1−イル]−メタノン。
【0008】
本発明はまた有効成分として式(I)で示される化合物を含む医薬組成物に関する。
【0009】
さらに、本発明の目的は、式(I)で示される化合物の合成、これらの化合物を含む医薬の化学的および医薬的製造、および、処置すべき哺乳動物(ヒトを含む)に本発明の化合物の式(I)で示される化合物の有効量をそのまままたは医薬製剤として投与することを特徴とするこれらの化合物による治療方法である。
【0010】
用語、"ハロゲン"置換基(上記で定義)は、フッ素、塩素、臭素またはヨウ素原子をいい、好ましくは、フッ素または塩素原子である。本発明の記載で用いられる用語、Cl−C4アルキル基は、メチル、エチル、ノルマル−およびイソプロピルおよび種々のブチル基を表す。これらのCl−C4アルキル基はCl−C4アルコキシ基中にあってもよい。用語C1−C6アルカノイルオキシ基は、水素原子ならびにC1−C6アルキル基およびこれに結合しているカルボニルオキシ基(−CO−O−)からなる1価のアシルオキシ基、好ましくは、ホルミルオキシ、アセトキシ、プロピオニルオキシ、種々のブチリルオキシ、バレロイルオキシおよびカプロイルオキシ基である。
【0011】
本発明はまた酸または塩基とともに形成される式(I)で示される塩に関する。
【0012】
有機および無機酸の両方とも酸付加塩の形成に用いることができる。適当な無機酸は、例えば、塩酸、硫酸およびリン酸である。1価の有機酸の代表例は、例えば、蟻酸、酢酸、プロピオン酸および種々の酪酸、吉草酸およびカプリン酸である。2価の有機酸の代表例は、例えば、シュウ酸、マロン酸、マレイン酸、フマール酸およびコハク酸であってもよい。他の有機酸、例えば、クエン酸、酒石酸などのヒドロキシ酸、または、例えば、安息香酸またはサリチル酸などの芳香族カルボン酸、並びに、メタンスルホン酸およびp−トルエンスルホン酸などの脂肪族および芳香族スルホン酸も用いることができる。特に有用な酸付加塩群は、酸成分自体が使用投与量では治療効果を示さないか、または活性成分の作用に望ましくない影響を与えないものである。これらの酸付加塩は医薬的に許容される酸付加塩である。本発明に属する医薬的に許容される酸付加塩に属さない酸付加塩とは、所与の場合に所望の化合物の精製および分離に都合がよい酸付加塩である。
【0013】
塩基とともに形成される塩のうち、特に重要なのは、例えば、ナトリウム、カリウムなどのアルカリ金属とともに形成される塩、例えば、カルシウムおよびマグネシウムなどのアルカリ土類金属とともに形成される塩、並びにアンモニアまたは有機アミンとともに形成される塩である。後者の塩基はさらに、例えば、ヒドロキシまたはアミノ基などの置換基を持ち、これらは、例えば、溶解性および生成物の取扱い性に影響を与える。
【0014】
本発明によって、式(I)で示される化合物は、式(II):
【化11】
[式中、R1、R2、R3、R4、XおよびYは、上記式(I)の定義と同じである]で示されるカルボン酸と、式(III):
【化12】
[式中、R5およびR6は、上記式(I)の定義と同じである]で示されるアミンとの間にアミド結合を形成させ、ついで、得られた式(I)[式中、R1、R2、R3、R4、R5、R6、XおよびYは、上記式(I)の定義と同じである]で示されるカルボン酸アミド誘導体を、所与の場合、新規な置換基を導入および/または既存の置換基の変更または除去、および/または塩形成および/または塩からの化合物の遊離によって、式(I)で示される別の化合物に変換するか、および/または得られたラセミ体を公知の方法によって光学活性な酸または塩基を用いて分割することを特徴とする方法によって合成される。
【0015】
アミド結合の生成は、好ましくは、式(II)で示されるカルボン酸からの活性誘導体を製造し、これを式(III)で示されるアミンと、好ましくは、塩基の存在下で反応させて行う。
【0016】
溶液中でカルボン酸の活性誘導体への変換は、適当な溶媒(例えば、ジメチルホルムアミド、アセトニトリル、塩素化炭化水素または炭化水素)中でアミド結合の形成中にインシチュで行う。活性誘導体は酸塩化物(例えば、カルボン酸と塩化チオニルから製造)、混合無水物(例えば、塩基、例えば、トリエチルアミン、の存在下、カルボン酸とイソブチルクロロホーメートから製造)、活性エステル(例えば、カルボン酸とヒドロキシべンズトリアゾールおよびジシクロヘキシル−カルボジイミドまたはО−べンズトリアゾール−1−イル−N,N,N',N'−テトラメチルウロニウムヘキサフルオロホスフェート(HBTU)から、塩基、例えば、トリエチルアミン、の存在下製造)であってもよい。活性誘導体は室温から0℃にて製造される。得られた溶液または懸濁液に、式(III)の適当なアミンを塩基として、または無機酸と形成させた塩として添加し、アミンの遊離のために必要な塩基、例えば、トリエチルアミンを別に反応混合物に添加する。縮合反応の後薄層クロマトグラフィーにかける。必要な反応時間は6−20hである。反応混合物の処理は種々の方法によって行い得る。
【0017】
反応混合物が懸濁液のとき、沈澱物を濾取し、適当な溶媒から再結晶させ、純粋な生成物を得る。もし、結晶化で純粋な生成物にならなければ、カラムクロマトグラフィーを精製のために用いることができる。カラムクロマトグラフィーは、吸着剤としてキーゼルゲル60、および溶出剤として、種々の溶媒系、例えば、トルエン/メタノール、クロロホルム/メタノールまたはトルエン/アセトンを用いる順相、またはPrep−Pak−500/C18型充填剤(Waters Associates製)、および溶出剤としてアセトニトリル/水/トリフルオロ酢酸を用いる逆相のいずれでも行い得る。もし、反応混合物がアシル化終了後溶液のとき、濃縮し、残渣を再結晶または上記に記載のカラムクロマトグラフィーによって精製する。生成物の構造は、IR、NMRおよびマススペクトロメトリーにより決定する。
【0018】
別法として、反応混合物は反応終了後、濃縮せずにカラムクロマトグラフィーによって精製し得る。所望の化合物を含む分画を濃縮し、残渣をジメチルスルホキシドに溶解させ、構造および純度および生成物の濃度をHPLC/MS(高圧カラムクロマトグラフィー後、マススペクトロメトリー)で決定する。
【0019】
得られた式(I)で示されるカルボン酸アミド誘導体は−製造方法とは別に−所与の場合、さらに置換基を導入、および/または変更、および/または既存の置換基の除去、および/または酸との塩の形成、および/または得られた酸付加物から塩基での処理による式(I)で示されるカルボン酸アミド誘導体の遊離によって、式(I)で示される他の化合物に変換することができ、および/または遊離の式(I)で示されるカルボン酸アミド誘導体は、塩基での処理により塩に変換できる。
【0020】
式(II)で示されるカルボン酸および式(III)で示される第1級または第2級アミンはいずれ市場から入手または種々の公知の方法によって合成することができる。市販されていない式(II)で示されるカルボン酸の合成は、実施例に記載されている。これらの方法に従って、他の市販されていない式(II)で示されるカルボン酸もまた製造することができる。
【0021】
本発明の化合物および医薬的に許容される塩はそのまま、または医薬組成物の形態で適切に用いることができる。これらの組成物(医薬)は、固体、液体または半流動体であってよく、当業界で通常用いられている医薬補助剤および添加剤、例えば、担体、補形剤、希釈剤、安定剤、湿潤または乳化剤、pH−および浸透圧調整剤、香味剤または芳香剤、および製剤化−促進または賦形剤を添加することができる。
【0022】
治療効果を示すのに必要な投与量は広い範囲で変えることができ、処置を受ける患者の疾患の程度、症状および体重、および有効成分に対する患者の感受性、投与経路、および一日当りの処置回数などによって変わる、具体的な症例毎の個々の条件に合わせることができる。用いられる有効成分の実際の投与量は、処置を受ける患者の情報によって当該分野の担当医によって安全に決定され得る。
【0023】
本発明の有効成分を含有する医薬組成物は、通常単位投与形態中有効成分0.01〜100mgを含む。ある種の組成物では当然有効成分の量は上記の上限または下限を超える場合があってもよい。
【0024】
固体の医薬組成物の形態は、例えば、錠剤、糖衣錠、カプセル、丸剤、注射坐の調製に用いられ得る凍結乾燥粉末アンプルであってよい。液状組成物は、注射および点滴剤、液剤、包装液剤および滴剤であってもよい:半流動組成物は、軟膏、香膏、クリーム、混合振盪剤および坐剤であってもよい。
【0025】
簡単に投与するために、医薬組成物は、1回に投与される有効成分の量、または2、3回分、または2分の1、3分の1または4分の1を含有する単位投与形態含むのが適している。そのような単位投与形態は、例えば、錠剤であり、錠剤を半分または4分の1にする溝にそって分割し、有効成分の正確な必要量を投与することができる。
【0026】
錠剤は酸−可溶層でコーティングし、胃を通過後有効成分含有量の放出を確実にすることができる。このような錠剤は腸溶化−コーティングされている。同様の効果は有効成分をカプセル封入することによっても行い得る。
【0027】
経口投与の医薬組成物は、例えば、賦形剤として、ラクトースまたは澱粉、結合剤または顆粒化剤として、ナトリウムカルボキシメチルセルローズ、メチルセルローズ、ポリビニルピロリジンまたは澱粉糊を含むことができる。じゃがいも澱粉または微結晶セルロースは崩壊剤として添加できるが、ウルトラアミロペクチンまたはホルムアルデヒドカゼインもまた用いることができる。タルク、珪酸コロイド、ステアリン、ステアリン酸カルシウムまたはマグネシウムは抗粘着剤および滑沢剤として用いることができる。
【0028】
錠剤は、例えば、湿式顆粒化後打錠によって製造することができる。有効成分、賦形剤および所与の場合に崩壊剤の一部の混合物を、適当な装置中で、結合剤の水性、アルコール性または水性アルコール性溶液とともに顆粒化し、ついで顆粒を乾燥させる。他の崩壊剤、滑沢剤、抗粘着剤を乾燥させた顆粒に添加し、混合物を錠剤に打錠する。所与の場合、錠剤には、投与を簡単にするために半分にする溝を入れる。
【0029】
錠剤は、有効成分および適当な添加剤の混合物から直接打錠することによって製造することができる。所与の場合、錠剤は医薬業界で通常用いられる添加物、砂糖、セルロース誘導体(メチル−またはエチルセルロース、ナトリウムカルボキシメチルセルロースなど)、ポリビニルピロリドン、リン酸カルシウム、炭酸カルシウム、食用着色剤、食用結着剤、芳香剤、酸化鉄色素などの安定剤、香味剤、着色剤、を用いて被覆することができる。カプセルの場合、有効成分および添加剤の混合物をカプセルに充填する。
【0030】
液体経口組成物は、例えば、懸濁剤、シロップ、エリキシルは、水、グリコール、油、アルコール、着色および香味剤を用いて製造することができる。
【0031】
直腸投与のための組成物は坐剤または浣腸に製剤化される。坐剤は有効成分以外に、担体、いわゆるアデプスプロサポジトリー(adeps pro suppository)を含むことができる。担体は、水素化植物油などの植物油、C12−C18脂肪酸のトリグリセリド(好ましくは、商品名ウイテプゾル(Witepsol)の担体)であってもよい。有効成分は溶融させたアデプスプロサポジトリーと均一に混和し、坐剤に成形する。
【0032】
非経口投与のための組成物は注射液に製剤化する。注射液の製造のために、有効成分を、蒸留水および/または、グリコエーテルなどの種々の有機溶媒に、所与の場合、例えば、ポリオキシエチレンソルビタン−モノラウレートまたはモノステアレート(ツイーン20、ツイーン60、ツイーン80)などの可溶化剤の存在下で溶解させる。注射液はまた、例えば、エチレンジアミンテトラアセテート、およびpH調整剤および緩衝剤および、所与の場合、例えば、リドカインなどの局所麻酔剤などの種々の添加剤を含有することができる。本発明の有効成分を含有する注射液は濾過され、アンプルに充填され、充填後滅菌される。
【0033】
もし、有効成分が吸湿性のとき、凍結乾燥によって安定化される。
式(I)で示されるカルボン酸アミド誘導体に構造的に良く似た類似化合物は文献で公知である。
【0034】
本発明の化合物と類似の置換インドール−2−イル−カルボニル−ピペリジン誘導体は、特許No.WO9618628および2種の刊行物[J. Med. Chem., 39,3769. (1996)、およびJ. Med. Chem., 42,4140. (1999)]に記載されている。逆転写阻害効果を有するこれらの化合物はAIDS患者に治療に用いられ得る。
【0035】
インドール−2−カルボン酸アミドもまたpp60C − SRCチロシンキナーゼを阻害することが公知[Bioorg. Med. Chem. Letters, 10, 483. (2000)]であり、従って、癌患者の治療に役立ち得る。刊行物はNMDA受容体拮抗作用については記載していない。
【0036】
ベンゾフラン−2−イル−ピペリジン誘導体は特許No.WO2000012074に記載されている。これらの化合物はp38−aキナーゼ阻害作用があり、従って、グラム−陰性菌による感染症および呼吸窮迫症候群にかかっている患者の治療に用いられ得る。
【0037】
Protein Sci., 6 (7), 1412. (1997)に記載のメタノン誘導体は、トロンビン阻害作用がある。刊行物はNMDA受容体拮抗作用については記載していない。
【0038】
驚くべきことに、この度、公知の事実に反して、構造的に類似する化合物−異なる酵素阻害作用のみがあることが知られている−本発明の式(I)で示される新規カルボン酸アミド誘導体が、NMDA(N−メチル−D−アスパルテート)受容体の優れて顕著かつ選択的拮抗剤であり、さらに、化合物の多くが、NMDA受容体のNR2Bサブタイプの選択的拮抗剤であることがわかった。化合物の望ましくない副作用がより少ないから、この選択的であることは重要である。
【0039】
NMDA受容体の拮抗剤は、中枢神経系における主な興奮性神経伝達物質であるグルタメートの過剰分泌に伴う多くの疾患に用いることができる。グルタメートによるNMDA受容体の過剰な活性化は細胞のカルシウム過剰供給を導き得る。これは細胞機能を変化させ、ニューロンの死活にさえ至り得る細胞内事象のカスケードを引き起こし得る[TINS, 10, 299−302 (1987)]。
【0040】
NMDA受容体の構造、機能および薬理学についての知識は、分子生物学の最近の業績によって拡大している。NMDA受容体は、少なくとも1つのNR1サブユニットおよび4つのNR2サブユニット(NR2A−D)の少なくとも1つから構成されるヘテロマーアセンブリーである。CNSおよび種々のNR2サブユニットから構成されるNMDA受容体の薬理学的感受性における2つの空間分布は異なる。これらのうち特に興味のあるのは、制限された分布(前脳および脊髄の膠様質における高い密度)からNR2Bサブユニットである。このサブタイプに選択的な化合物は入手可能であり[Curr. Pharm. Des. 5, 38−404 (1999)]、脳卒中[Stroke 28, 2244−2251 (1997)]、外傷性脳損傷[Brain Res. 792, 291−298 (1998)]、パーキンソン病[Exp. Neurol. 163, 239−243 (2000)]、神経障害性および炎症性疼痛[Neuropharmacology 38, 611−623 (1999)]の動物モデルで有効であることが証明されている。NMDA受容体のサブタイプ選択的拮抗剤は、グルタメート結合部位またはチャンネル細孔内に作用するNMDA受容体の非−選択的拮抗剤によって生じる面倒な副作用を殆どまたは全く示さないと予想される。
【0041】
NMDA拮抗剤に応答することが知られている疾患[Drug News Perspect 11, 523−569 (1998)およびWO 00/00197国際特許出願]は、なんらかの理由(例えば、脳卒中、心臓手術)による脳虚血、アルツハイマー病などのなどの慢性神経変性疾患、パーキンソン病、筋萎縮性側索硬化症(ALS)、ハンチントン病、ヒト免疫不全ウイルス(HIV)関連神経損傷、外傷性脳または脊髄損傷、疼痛(例えば、外傷後または術後)、および慢性的疼痛症状、例えば神経因性疼痛または癌関連疼痛である。NMDA受容体拮抗剤はまた、癲癇、不安、うつ、偏頭痛、精神病、筋肉攣縮、多発梗塞性痴呆、他に由来する痴呆、低血糖、網膜変性疾患(例えば、CMV網膜変性疾患)、喘息、耳鳴り、アミノ配糖体抗生物質−誘導聴覚損失に用いられ得る。NMDA拮抗剤は、疼痛のオピオイド治療に対する寛容および/または依存の軽減および、例えば、アルコール、オピオイドおよびコカインの禁断症状に用いられ得る。
【0042】
標的化合物は上記の生物学的作用をもっているから、本発明の目的はまた、式(I)で示されるカルボン酸アミド誘導体またはそれらの塩による処置方法であり、処置されるべき哺乳動物−ヒトを含む−本発明の式(I)で示される化合物の有効量をそのまま、または医薬として投与するものである。
【0043】
出生後の発達中に、神経細胞のNMDA受容体のサブユニット組成物は変化しつつある。同様の変化は細胞培養物でも検出された[Eur. J. Neurosci. 10, 1704-1715 (1998)]。文献のデータおよび発明者らの免疫−細胞化学試験によれば、インビトロで4−7日間培養された神経細胞は、NR1サブユニットとともに主にNR2Bサブユニットを発現する。これらの細胞中のNMDA拮抗性の機能試験はほとんどNR2Bサブユニット含有受容体に対する作用を反映する。NMDA受容体は興奮時にはカルシウムイオンを通過し得ることが知られているから、細胞に拮抗剤(NMDA)投与後、細胞内カルシウム濃度の上昇の測定によってNMDA受容体の活性化を測定した。
【0044】
プレートリーダー蛍光計による細胞内カルシウム濃度の測定によるインビトロNMDA拮抗強度の評価
細胞内カルシウム測定は17日齢のチャールズリバーラットの胎芽から誘導した初代新皮質細胞培養物で行った(新皮質細胞培養物の調製はJohnson, M.I.; Bunge, R. P. (1992): Primary cell cultures of peripheral and central neurons and glia. In: Protocols for Neural Cell Culture, eds: Fedoroff, S.; Richardson A., The Humana Press Inc., 13−38参照)。分離後、細胞を標準的な96−ウェルマイクロプレートに播種し、培養物をカルシウムの測定まで95%空気−5%CO2の雰囲気で37℃に維持した。
【0045】
培養物はインビトロで4−7日後、細胞内カルシウム測定に用いた。測定前に、細胞に蛍光Ca2+−感受性色素、Fluo−4/AM(2−2.5pM)を負荷した。負荷を止めるために、細胞を測定用の溶液で2回洗滌した(140 mM NaCl、5 mM KCl、2 mM CaCl2、5 mM HEPES、5 mM HEPES−Na、20 mM グルコース、10 μM glycine, pH=7.4)。洗滌後、被験化合物を上記溶液中細胞に添加した(90 μl/ウェル)。細胞内カルシウム測定はプレートリーダー蛍光計で行った:フルオ−4−フルオルセンスなどの上昇、分子内カルシウムを40μM NMDAの添加によって誘導した。被験化合物の阻害強度は当該化合物の種々の濃度の存在下でカルシウムの上昇の減少の測定によって評価した。測定後、標準的な検量曲線をわずかな修正を加えて作成し、蛍光データをカルシウム濃度値に変換し用いた[Meth. Cell. Biol. 40, 155−181 (1994)]。
【0046】
投与量−応答曲線およびIC50−値を少なくとも3つの独立した実験から得られたデータを用いて計算した。1つの濃度における阻害強度はNMDA応答の阻害パーセントとして表した。S字状の濃度−阻害曲線がデータに合致し、IC50値は化合物による最大阻害の半分を示す濃度として測定した。
【0047】
Table1中の本発明のこの試験で測定された最も有効な化合物のIC50値を表に挙げ(1−2欄)、それとともに試験を行った最も有効な対照化合物も挙げた(3−4欄)。
【0048】
【表1】
【0049】
下記は対照化合物である:
Co 101244:1−[2−(4−ヒドロキシフェノキシ)エチル]−4−ヒドロキシ−4−(4−メチルベンジル)ピペリジン
EMD 95885:6−[3−(4−フルオロベンジル)ピペリジン−1−イル]プロピオニル]−2,3−ジヒドロ−ベンズオキサゾール−2−オン
CP−101,606:(1S,2S)−1−(4−ヒドロキシフェニル)−2−(4−ヒドロキシ−4−フェニルピペリジン−1−イル)−1−プロパノール
Co−111103:1−[2−(4−ヒドロキシフェノキシ)エチル]−4−(4−フルオロベンジル)ピペリジン
Ro 256981:R−(R*,S*)−1−(4−ヒドロキシフェニル)−2−メチル−3−[4−(フェニルメチル)ピペリジン−1−イル]−1−プロパノール
【0050】
Table1に示すように、本発明の化合物の多くは試験に用いた公知の対照化合物の強度を超えている。
【0051】
組換えラットNMDA受容体を発現する細胞に対するサブユニット選択性試験
化合物のNR2Bサブユニット選択性を証明するために、ラットNRlaおよびNR2A、またはNR2BサブユニットのcDNAで形質移入した細胞を用いた。刊行物記載の配列によってクローニングされた遺伝子[gi508809 (rat NRla)、gi205738(rat NR2B), gi2905805 (rat NR2A)]を種々の抵抗性遺伝子(NRlaの場合はハイグロマイシンまたはNR2サブユニットの場合はネオマイシン)を坦持する誘導可能な哺乳動物発現ベクターに挿入した。構築ベクターを、カチオン脂質形質移入法を用いてHEK293細胞に導入した。タンパク質発現は3μMムリステロンAによって誘導された。細胞を試験前365pMケタミンの存在下48−75時間95%空気−5%CO2の雰囲気下37℃にて維持した。
【0052】
NRl a /NR2Bサブユニットで形質移入した細胞のNMDA拮抗性強度の評価−蛍光法
NRla/NR2B受容体を安定して発現する細胞の確立のために、形質移入細胞を選択抗生物質に4週間暴露させ、抵抗性のあるクローンを生長させた。NR2Bサブユニットタンパク質の発現は免疫細胞化学法に基づく流動細胞計測法によって証明した。陽性のクローンをさらに、パッチクランプ実験法で機能活性について試験した。最高のNMDA誘発イオン−電流を産生する最良クローンを、細胞質ゾルのカルシウム濃度のNMDA誘導上昇の測定によるNMDA拮抗性を試験するために用いた。細胞のタンパク質発現および維持の誘導は上記と同様である。
【0053】
細胞を標準的な96−ウェルマイクロプレートに播種した。NMDA拮抗性測定のためにプレートリーダー−蛍光試験法を用いた。この方法は本質的にラット皮質ニューロンの初代培養物試験について上記に記載の方法と同様である。
【0054】
NRl a /NR2Aサブユニットで形質移入した細胞のNMDA拮抗性強度の評価−パッチクランプ法
NRla/NR2A受容体を一時的に発現し、カバーグラス上で生長させた細胞をパッチクランプ実験に用いた。標準的な技術によって全−細胞パッチクランプを記録した。細胞培養物は持続的に細胞外液(140 mM NaCl, 5 mM KCl, 5 mM Hepes, 5 mM Na−Hepes, 2 mM CaCl2, 20 mM グルコース, 10 μM グリシン, pH 7.35)を室温にて潅流させた。3〜6MΩ間の抵抗をもったパッチピペットを細胞内液(140mM CsCl, 11 mM EGTA, および10 mM Hepes, pH 7.3)で満たした。100 μM NMDAで誘導された内部電流を、細胞から−70 mVの電圧固定を記録した。化合物は電磁石バルブで調節されるマルチバレル注射器を用いて添加した。最初にNMDAは応答が安定するまで繰り返し投与され、その後、被験化合物の存在下で添加した。阻害程度−パーセントで表示−は、被験化合物の存在下および不存在下でNMDAで誘導された最高電流から計算された。選択性率(NR2B/NR2A)は、NR1/2A形質移入細胞に対する試験投与量およびNR1/NR2B発現細胞に対するNMDA拮抗性のIC50値の比率として計算した。
【0055】
結果をTable2に示す。
【表2】
【0056】
*:プレートリーダー蛍光法による細胞内カルシウム濃度の測定によるNRla/NR2Bサブユニットを安定的に発現するHEK293細胞で得られたデータ。3つの実験の平均。
**:一時的NRla/NR2A形質移入HEK細胞でのパッチクランプ実験の結果。
試験濃度は指示されたものである。3、6、2の実験の平均が、4570001461、4570002260およびCP−101,606でそれぞれ示されている。
選択性:選択性率(NR2B/NR2A)、NR1/2A形質移入細胞での試験濃度およびNR1/NR2B発現細胞でのIC50値の比率
【0057】
Table2の結果によれば、化合物4570001461および4570002260並びにCP−101,606は、NR2Bサブユニット含有NMDA受容体に対して高い選択性を示した。
【0058】
本発明の化合物および医薬組成物の合成を、限定する目的ではない下記の実施例によって具体的に説明する。生物学的実験で引用される化合物の番号は、実施例で製造された化合物の名称に従っている。
【0059】
実施例1
6− [ 1− ( 4−ベンジルピペリジン−1−イル ) メタノイル ] −3H−フロ [ 2 , 3− f] ベンズオキサゾール−2−オン (45 14255)
a) 3H−フロ [ 2 , 3− f] ベンズオキサゾール−2−オン−6−カルボン酸エチル
5−ヒドロキシ−6−アミノベンゾフラン−2−カルボン酸エチル[Helv. Chim. Acta 77, 100. (1994)]0.9 g(4.2 mmol)、テトラヒドロフラン60 ml、20%ホスゲンのトルエン溶液3.1 mlおよびトリエチルアミン2.0 mlの混合物を室温にて1 h攪拌した。テトラヒドロフランを真空にて留去し、残渣に水を添加し、生成物を酢酸エチルで抽出した。一緒にした有機層を5 %炭酸水素ナトリウム水溶液、水、1N 塩酸水溶液および再度水で洗滌し、硫酸ナトリウムで乾燥させ、濃縮し、標題化合物1.0 g(96 %)を油状物質として得た。
【0060】
b) 3H−フロ [ 2 , 3− f] ベンズオキサゾール−2−オン−6−カルボン酸
3H−フロ[2,3−f]ベンズオキサゾール−2−オン−6−カルボン酸エチル1.0 g(4 mmol)、エタノール100 mlおよび水酸化カリウム0.5 gの混合物を1 h還流させた。混合物を濃縮し、残渣を水に溶解させ、20 %硫酸水溶液にて酸性にした。析出した結晶を濾取し、水で洗滌し、標題化合物0.84 g(95 %)を得た。
Mp.:190−192℃(水)
【0061】
c) 6− [ 1− ( 4−ベンジルピペリジン−1−イル ) メタノイル ] 3H−フロ [ 2 , 3− f] ベンズオキサゾール−2−オン
標題化合物を3H−フロ[2,3−f]ベンズオキサゾール−2−オン−6−カルボン酸および4−ベンジルピペリジンから実施例4に記載の方法に従って製造した。
Mp.:123−125℃(ジエチルエーテル)
【0062】
実施例2
6− [ 1− ( 4−ベンジルオキシピペリジン−1−イル ) メタノイル ] −3H−フロ [ 2 , 3− f] ベンズオキサゾール−2−オン (45 14254)
標題化合物を3H−フロ[2,3−f]ベンズオキサゾール−2−オン−6−カルボン酸および4−ベンジルオキシピペリジンから実施例4に記載の方法に従って製造した。
Mp.:217−219℃(ジエチルエーテル)
【0063】
実施例3
1− ( 4−ベンジルピペリジン−1−イル ) −1− ( 1 , 6−ジヒドロ−1 , 6−ジアザ− as −インダセン−2−イル ) メタノン (45 14305)
a)( Z ) −2−アジド−3− ( 1−インドール−5−イル ) アクリル酸メチル
窒素気流中、ナトリウムメトキシド溶液(メタノール15 mlおよびナトリウム0.66 g(29 mmol)から調製)に、インドール−5−カルバルデヒド[Helv. Chim. Acta, 1616. (1968)]1.02 g(7 mmol)、アジド−酢酸メチル3.34 g(29 mmol)およびメタノール7 mlの混合物を滴下しながら0 ℃にて添加し、得られた混合物をその温度で5 h攪拌した。ついで、反応混合物を水50 mlで希釈し、クロロホルム50 mlを用いて3回抽出した。一緒にした有機層を水20 mlで洗滌し、層分離ろ紙でろ過し、濃縮し、標題化合物1.3 g(77 %)を得た。
Mp.:130−133℃(クロロホルム)
【0064】
b) 1 , 6−ジヒドロ−1 , 6−ジアザ− as −インダセン−2−カルボン酸メチル
キシレン36 mlの沸騰溶液に、(Z)−2−アジド−3−(1H−インドール−5−イル)アクリル酸メチル1.09 g(4.5 mmol)を少しずつ添加した。反応混合物を窒素ガスの生成が終了するまで還流させ、ついで、濃縮し、残渣をヘキサンで再結晶させ、生成物をろ過し、ヘキサンで洗滌し、標題化合物0.6 g(62 %)を得た。
Mp.:183−184℃(ヘキサン)
【0065】
c) 1 , 6−ジヒドロ−1 , 6−ジアザ− as −インダセン−2−カルボン酸
1,6−ジヒドロ−1,6−ジアザ−as−インダセン−2−カルボン酸メチル0.53 g(2.5 mmol)、トリメチルシラノール酸カリウム(Aldrich)0.36 g(2.5 mmol)およびテトラヒドロフラン6.0 mlの混合物を1 h還流させ、さらに、トリメチルシラノール酸カリウム0.18 g(1.25 mmol)を添加し、5 h還流後、反応混合物を濃縮した。残渣を水20 mlと混合し、不溶物を濾取し、塩酸0.32 mlをろ液に添加し、析出した粗生成物を濾取し、吸着剤として、キーゼルゲル60(Merck)および溶出剤として、クロロホルム:メタノール=9:1を用いて、カラムクロマトグラフィーにより精製した。生成物をジエチルエーテルで結晶化し、標題化合物0.22 g(44 %)を得た。
Mp.:248−250℃(ジエチルエーテル)
【0066】
d) 1− ( 4−ベンジルピペリジン−1−イル ) −1− ( 1 , 6−ジヒドロ−1 , 6−ジアザ− as −インダセン−2−イル ) メタノン
標題化合物を1,6−ジヒドロ−1,6−ジアザ−as−インダセン−2−カルボン酸および4−ベンジルピペリジンから実施例4に記載の方法に従って製造した。
Mp.:186−188℃(ジエチルエーテル)
【0067】
実施例4
1− ( 4−ベンジルピペリジン−1−イル ) −1− ( 6−ヒドロキシ−1H−インドール−2−イル ) メタノン (45 13579 )
6−ヒドロキシ−インドール−2−カルボン酸[J. Chem. Soc. 1605−1608. (1948)] 5.0 g (28.2 mmol)、トリエチルアミン4.4 ml (31.6 mmol)、4−ベンジルピペリジン5.0 g (28.5 mmol)、HBTU(Advanced Chem. Tech.)12.0 g (31.6 mmol)およびジメチルホルムアミド50 mlの混合物を室温にて6 h攪拌した。沈澱生成物をろ取し、エタノールから再結晶させ、標題化合物6.75 g (71 %)を得た。Mp: 214−215℃(エタノール)。
【0068】
実施例5
1− [ 4− ( 4−フルオロベンジル ) ピペリジン−1−イル ] −1− ( 6−ヒドロキシ−1H−インドール−2−イル ) メタノン (45 13848)
標題化合物をアセトニトリル中4−(4−フルオロベンジル)ピペリジン[J. Med. Chem., 35, 4903. (1992)]および6−ヒドロキシ−1H−インドール−2−カルボン酸から室温にて製造した。反応混合物を濃縮し、残渣を吸着剤としてKieselgel 60(Merck)を用い、トルエン:メタノール=4:1を溶出剤としてカラムクロマトグラフィーより精製した。Mp.: 180−182℃(トルエン)。
【0069】
実施例6
1− ( 4−ベンジルピペリジン−1−イル ) −1− ( 5−ニトロ−1H−インドール−2−イル ) メタノン (45 14205)
標題化合物を5−ニトロインドール−2−カルボン酸(J. Am. Chem. Soc., 4621 (1958)]および4−ベンジルピペリジンから実施例4に記載の方法に従って製造した。Mp.: 220−224℃(ジエチルエーテル)。
【0070】
実施例7
1− ( 5−アミノ−1H−インドール−2−イル ) −1− ( 4−ベンジルピペリジン−1−イル ) メタノン (45 14244)
1−(4−ベンジルピペリジン−1−イル)−1−(5−ニトロ−1H−インドール−2−イル)メタノン0.5 g (1.38 mmol)、メタノール20 mlおよび10 %Pd/C触媒0.1 gの混合物を5 h水素添加した。触媒をろ取し、メタノールで洗滌し、ろ液を濃縮した。残渣ジエチルエーテルで処理し、沈澱生成物をろ取した。標題化合物0.27 g (59 %)を得た。Mp.: 175−180℃(ジエチルエーテル)。
【0071】
実施例8
( 4−ベンジルピペリジン−1−イル ) − ( 6−ヒドロキシ−1H−ベンゾイミダゾ l −2−イル ) −メタノン (45 70001103)
a) N−ブチル−N ' − ( 4−メトキシ−2−ニトロ−フェニル ) オキザルアミド
N−(4−メトキシ−2−ニトロ−フェニル)オキザロアミン酸エチルエステル[J. Med. Chem., 18, 926 (1975)]44.0 g (164 mmol)およびトルエン330 mlの懸濁液に、N−ブチルアミン16.8 ml (170 mmol)を20℃にて添加した。反応混合物室温にて10 h攪拌し、ついで、濃縮し、残渣をジエチルエーテルで結晶化し、沈澱生成物をろ取し、ジエチルエーテルで洗滌し、乾燥させ、標題化合物45.3 g (93.3 %)を得た。Mp.: 127−128℃(ジエチルエーテル)。
【0072】
b) N− ( 2−アミノ−4−メトキシ−フェニル ) −N ' −ブチル−オキザルアミド
A mixture ofN−ブチル−N'−(4−メトキシ−2−ニトロ−フェニル)オキザルアミド27.0 g (91 mmol)、メタノール1200 mlおよび5%Pd/C触媒7.3 gの混合物を3 h水素添加した。反応混合物にアセトン600 mlを添加した。触媒をろ取し、アセトンで洗滌し、ろ液を濃縮し、残渣をジエチルエーテルで結晶化させた。標題化合物21.8 g (90.1 %)を得た。Mp.: 180−181℃(ジエチルエーテル)。
【0073】
c) 6−メトキシ−1H−ベンズイミダゾール−2−カルボン酸 ブチルアミド
窒素雰囲気下、N−(2−アミノ−4−メトキシ−フェニル)−N'−ブチル−オキザルアミド41.0 g (154 mmol)を240℃にて10 min攪拌した。混合物を室温まで冷却し、ついで、アセトン300 mlを添加し、1 h攪拌した。沈澱生成物をろ取し、ろ液を濃縮し、残渣をN−ヘキサン150 mlと混和した。沈澱生成物をろ取し、ヘキサンで洗滌し、乾燥させ、標題化合物26.5 g (69.5 %)を得た。Mp.: 125−126℃(N−ヘキサン)。
【0074】
d) 6−ヒドロキシ−1H−ベンズイミダゾール−2−カルボン酸
6−メトキシ−1H−ベンズイミダゾール−2−カルボン酸ブチルアミド26.0 g (105 mmol)および48 %臭化水素酸水溶液780 mlを110℃にて8 h攪拌し、ついで、12 h還流させた。混合物を室温まで冷却しし、沈澱生成物をろ取し、水でpHが中性になるまで洗滌し、乾燥させ、標題化合物14.3 g (76.2 %)を得た。Mp.: 206−207℃(水)。
【0075】
e)( 4−ベンジルピペリジン−1−イル ) − ( 6−ヒドロキシ−1H−ベンズイミダゾール−2−イル ) −メタノン (45 70001103)
6−ヒドロキシ−1H−ベンズイミダゾール−2−カルボン酸3.0 g (16.75 mmol)、トリエチルアミン2.4 ml (17.2 mmol)、4−ベンジル−ピペリジン3.0 g (17.1 mmol)、HBTU7.0 g (18.5 mmol)およびジメチルホルムアミド100 mlの混合物を室温にて16 h攪拌した。反応混合物を濃縮し、残渣を、吸着剤としてKieselgel 60(Merck)を用い、トルエン:メタノール=4:1を溶出剤としてカラムクロマトグラフィーにより精製し、ついで、トルエンから再結晶し、標題化合物3.58 g (63.5 %)を得た。Mp.: 186℃(トルエン)。
【0076】
実施例9
( 6−ヒドロキシ−1H−ベンズイミダゾール−2−イル ) − [ 4− ( 4−メチル−ベンジル ) −ピペリジン−1−イル ] −メタノン (45 70001378)
標題化合物を6−ヒドロキシ−1H−ベンズイミダゾール−2−カルボン酸[実施例8の d )]および4−(4−メチルベンジル)ピペリジン [J.Org. Chem., 64, 3763 (1999)]から実施例4に記載の方法に従って製造した。Mp.: 93℃(ジイソプロピルエーテル)。
【0077】
実施例10
医薬組成物の製造:
a) 錠剤:
有効成分0.01−50 %、乳糖15−50 %、ジャガイモデンプン15−50 %、ポリビニルピロリドン5−15 %、タルク1−5 %、ステアリン酸マグネシウム0.01−3 %、コロイド二酸化ケイ素1−3 %およびウルトラアミロペクチン2−7 %を混合し、ついで、湿式顆粒により顆粒化し、打錠した。
【0078】
b) 糖衣錠、膜被覆錠剤:
上記の方法で製造した錠剤を腸−または胃−溶膜からなる層または砂糖およびタルクでコーティングした。糖衣錠を蜜蝋およびカルナバ蝋の混合物で艶出しした。
【0079】
c) カプセル:
有効成分0.01−50 %、ラウリル硫酸ナトリウム1−5 %、デンプン15−50 %、乳糖15−50 %、コロイド二酸化ケイ素1−3 %およびステアリン酸マグネシウム0.001−3 %を完全に混合し、混合物を篩にかけ、硬ゼラチンカプセルに充填した。
【0080】
d) 懸濁液:
成分:有効成分0.01−15 %、水酸化ナトリウム0.1−2 %、クエン酸0.1−3 %、ニパギン(メチル−4−ヒドロキシ安息香酸ナトリウム)0.1−3 %、ニパソール0.005−0.02 %、カルボポール(ポリアクリル酸)0.01−0.5 %、96 % エタノール0.1−5 %、香味料0.1−1 %、ソルビトール(70 % 水溶液)20−70 %および蒸留水30−50 %。
【0081】
蒸留水20 ml中ニパギンおよびクエン酸の溶液に、激しく攪拌しながらカルボポールを少しずつ添加し、溶液を10−12 h放置した。ついで、蒸留水1 ml中水酸化ナトリウム、ソルビトールの水溶液および最後にエタノール性キイチゴ香料を攪拌しながら添加した。ついで、この担体に有効成分を少しずつ添加し、投げ込みホモジナイザーで懸濁させた。最後に、所望の最終容量まで蒸留水を添加し、懸濁シロップをコロイドミリング装置を通過させた。
【0082】
e) 坐剤:
各坐剤について、有効成分0.01−15%および乳糖1−20%を完全に混合し、ついで、アデプスプロサポジトリー(adeps pro suppository、例えば、Witepsol 4)50−95%を溶解させ、35 ℃に冷却し、有効成分および乳糖の混合物をその中にホモジナイザーで混合し、得られた混合物を冷却・成型した。
【0083】
f) 凍結乾燥粉末製剤:
注射剤用にマンニトールまたは乳糖の5 %溶液を蒸留水で調製し、溶液をろ過し、滅菌溶液とした。有効成分0.01−5 %の溶液も注射剤用の蒸留水で調製し、この溶液をろ過し、滅菌溶液とした。これら2種の溶液を無菌状態で混合し、1 mlずつアンプルに充填し、アンプルの内容物を凍結乾燥させ、アンプルを窒素気流中密封した。投与前に、アンプルの内容物を滅菌水または0.9 %(生理的)滅菌塩化ナトリウム水溶液に溶解させる。[0001]
The present invention relates to a compound of formula (I):
[Chemical 9]
[Where
R1, R2, RThreeAnd RFourOne of -OH or -NH2A group, the other is a hydrogen atom, or
[0002]
Two adjacent R1, R2, RThreeAnd RFourA group may be, where given, one or more of the same or different additional heteroatoms and —CH═ and / or —CH2Together with the group forms a 5-6 membered homo- or heterocycle, preferably a pyrrole, pyrazole, imidazole, oxazole, oxo-oxazolidine, or 3-oxo-1,4-oxazine ring, and R1, R2, RThreeAnd RFourThe other two of the groups are hydrogen atoms,
[0003]
RFiveAnd R6Together with the nitrogen atom between them forms a saturated or unsaturated 4-6 membered heterocycle, which is a hydroxy group and / or, in the given case, phenyl or phenoxy, phenyl- (Cl-CFourAlkyl), phenyl- (Cl-CFourAlkoxy), phenoxy- (Cl-CFourAlkyl), anilino, phenyl- (Cl-CFourAlkylamino), [phenyl- (Cl-CFourAlkyl)]-amino, benzoyl, hydroxy-diphenylmethyl, Cl-CFourAn alkoxycarbonyl-phenoxymethyl or benzhydridene group wherein the aromatic ring is optionally one or more halogen atoms, cyano or hydroxy groups, Cl-CFourAlkyl or Cl-CFourSubstituted with an alkoxy group),
[0004]
The meanings of X and Y are independently an oxygen or nitrogen atom, or —CH═]
NMDA receptor antagonist carboxylic acid amide derivatives, and their salts formed with acids and bases.
[0005]
The present invention also relates to a salt of a compound of formula (I) formed by an acid or base, in particular a salt formed by a pharmaceutically acceptable acid or base. Unless otherwise specified, the meaning of the compound represented by) is either a free compound or a salt.
[0006]
A particularly important group of compounds of the invention is of formula (Ia):
[Chemical Formula 10]
[Wherein R1, R2, RThree, RFour, RFiveAnd R6Is the same as described for the compound of formula (I)].
[0007]
Particularly important carboxylic acid amide derivatives of the formula (I) are:
1- (4-benzyloxypiperidin-1-yl) -1- (6-hydroxy-1H-indol-2-yl) methanone,
1- (4-benzylpiperidin-1-yl) -1- (4-hydroxy-1H-indol-2-yl) methanone,
1- (4-benzylpiperidin-1-yl) -1- (6-hydroxy-1H-indol-2-yl) methanone,
1- (4-benzylpiperidin-1-yl) -1- (5-hydroxy-1H-indol-2-yl) methanone,
1- (6-hydroxy-1H-indol-2-yl) -1- [4- (4-methylbenzyloxy) piperidin-1-yl)] methanone,
1- (6-hydroxy-1H-indol-2-yl) -1- (4-phenoxymethylpiperidin-1-yl) methanone,
1- (6-hydroxy-1H-indol-2-yl) -1- [4- (4-methylbenzyl) -4-hydroxypiperidin-1-yl)] methanone,
1- [4- (4-fluorobenzylpiperidin-1-yl)]-1- (6-hydroxy-1H-indol-2-yl) methanone,
1- (6-hydroxy-1H-indol-2-yl) -1- (4-phenoxypiperidin-1-yl) methanone,
1- [4- (4-fluorobenzylpiperidin-1-yl)]-1- (5-hydroxy-1H-indol-2-yl) methanone,
1- (4-hydroxy-1H-indol-2-yl) -1- (4-phenoxymethylpiperidin-1-yl) methanone,
1- (6-hydroxy-1H-indol-2-yl) -1- (4-phenoxy-3,6-dihydro-2H-pyridin-1-yl) methanone,
1- (4-benzyloxypyrrolidin-1-yl) -1- (6-hydroxy-1H-indol-2-yl) methanone,
1- [4- (4-chlorobenzyloxy) -piperidin-1-yl)]-1- (6-hydroxy-1H-indol-2-yl) methanone,
(4-benzylpiperidin-1-yl)-(6-hydroxy-1H-benzimidazol-2-yl) -methanone, and
(6-Hydroxy-1H-benzimidazol-2-yl)-[4- (4-methyl-benzyl) -piperidin-1-yl] -methanone.
[0008]
The invention also relates to a pharmaceutical composition comprising a compound of formula (I) as an active ingredient.
[0009]
Furthermore, the object of the present invention is the synthesis of the compounds of formula (I), the chemical and pharmaceutical production of medicaments containing these compounds and the compounds of the invention in mammals (including humans) to be treated. A therapeutic method using these compounds, which comprises administering an effective amount of the compound represented by the formula (I) as it is or as a pharmaceutical preparation.
[0010]
The term “halogen” substituent (defined above) refers to a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom. The term used in the description of the present invention, Cl-CFourAlkyl groups represent methyl, ethyl, normal- and isopropyl and various butyl groups. These Cl-CFourThe alkyl group is Cl-CFourIt may be in an alkoxy group. Term C1-C6The alkanoyloxy group includes a hydrogen atom and C1-C6A monovalent acyloxy group consisting of an alkyl group and a carbonyloxy group (—CO—O—) bonded thereto, preferably formyloxy, acetoxy, propionyloxy, various butyryloxy, valeroyloxy and caproyloxy groups .
[0011]
The invention also relates to a salt of formula (I) formed with an acid or base.
[0012]
Both organic and inorganic acids can be used to form acid addition salts. Suitable inorganic acids are, for example, hydrochloric acid, sulfuric acid and phosphoric acid. Representative examples of monovalent organic acids are formic acid, acetic acid, propionic acid and various butyric acids, valeric acid and capric acid. Representative examples of the divalent organic acid may be, for example, oxalic acid, malonic acid, maleic acid, fumaric acid and succinic acid. Other organic acids, such as hydroxy acids such as citric acid, tartaric acid, or aromatic carboxylic acids such as benzoic acid or salicylic acid, and aliphatic and aromatic sulfones such as methanesulfonic acid and p-toluenesulfonic acid Acids can also be used. A particularly useful acid addition salt group is one in which the acid component itself does not exhibit a therapeutic effect at the dosage used or does not undesirably affect the action of the active ingredient. These acid addition salts are pharmaceutically acceptable acid addition salts. An acid addition salt that does not belong to the pharmaceutically acceptable acid addition salts belonging to the present invention is an acid addition salt that is convenient for purification and separation of the desired compound in a given case.
[0013]
Of particular importance among the salts formed with bases are, for example, salts formed with alkali metals such as sodium and potassium, for example salts formed with alkaline earth metals such as calcium and magnesium, and ammonia or organic amines. It is a salt formed together. The latter bases further have substituents such as, for example, hydroxy or amino groups, which affect, for example, solubility and product handling.
[0014]
According to the present invention, the compound of formula (I) is represented by formula (II):
Embedded image
[Wherein R1, R2, RThree, RFour, X and Y are the same as defined in the above formula (I)], and the formula (III):
Embedded image
[Wherein RFiveAnd R6Is the same as defined in the above formula (I)], an amide bond is formed with the amine of the formula (I), and then the resulting formula (I) [wherein R1, R2, RThree, RFour, RFive, R6, X and Y are the same as defined above for formula (I)], in a given case, introducing a new substituent and / or modifying or removing an existing substituent, And / or salt formation and / or liberation of the compound from the salt to convert it to another compound of formula (I) and / or the resulting racemate is optically active acid or base by known methods Is synthesized by a method characterized by dividing using.
[0015]
Formation of the amide bond is preferably carried out by preparing an active derivative from a carboxylic acid of formula (II) and reacting it with an amine of formula (III), preferably in the presence of a base. .
[0016]
Conversion of the carboxylic acid to the active derivative in solution takes place in situ during the formation of the amide bond in a suitable solvent (eg dimethylformamide, acetonitrile, chlorinated hydrocarbon or hydrocarbon). Active derivatives are acid chlorides (e.g. prepared from carboxylic acid and thionyl chloride), mixed anhydrides (e.g. prepared from carboxylic acid and isobutyl chloroformate in the presence of a base such as triethylamine), active esters (e.g. From carboxylic acids and hydroxybenztriazole and dicyclohexyl-carbodiimide or O-benstriazol-1-yl-N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU), bases such as triethylamine, In the presence of The active derivative is produced from room temperature to 0 ° C. To the resulting solution or suspension, the appropriate amine of formula (III) is added as a base or as a salt formed with an inorganic acid and separately reacted with the base necessary for the liberation of the amine, for example triethylamine. Add to mixture. The condensation reaction is followed by thin layer chromatography. The required reaction time is 6-20 h. The reaction mixture can be processed by various methods.
[0017]
When the reaction mixture is a suspension, the precipitate is filtered and recrystallized from a suitable solvent to give the pure product. If crystallization does not result in a pure product, column chromatography can be used for purification. Column chromatography is based on Kieselgel 60 as the adsorbent and normal phase using various solvent systems such as toluene / methanol, chloroform / methanol or toluene / acetone as the eluent, or Prep-Pak-500 / C18 type packing material. (Waters Associates) and reverse phase using acetonitrile / water / trifluoroacetic acid as eluent. If the reaction mixture is a solution after completion of acylation, it is concentrated and the residue is purified by recrystallization or column chromatography as described above. The product structure is determined by IR, NMR and mass spectrometry.
[0018]
Alternatively, the reaction mixture can be purified by column chromatography after completion of the reaction without concentrating. Fractions containing the desired compound are concentrated, the residue is dissolved in dimethyl sulfoxide, and structure and purity and product concentration are determined by HPLC / MS (high pressure column chromatography followed by mass spectrometry).
[0019]
The resulting carboxylic acid amide derivative of the formula (I) —in addition to the production process—in a given case, introduces and / or modifies further substituents and / or removes existing substituents, and / or Alternatively, conversion to other compounds of formula (I) by formation of salts with acids and / or liberation of the carboxylic acid amide derivatives of formula (I) from the resulting acid adducts by treatment with bases And / or the free carboxylic acid amide derivative of formula (I) can be converted to a salt by treatment with a base.
[0020]
The carboxylic acid represented by the formula (II) and the primary or secondary amine represented by the formula (III) can be obtained from the market or synthesized by various known methods. The synthesis of carboxylic acids of formula (II) which are not commercially available is described in the examples. According to these methods, other non-commercial carboxylic acids of formula (II) can also be prepared.
[0021]
The compounds and pharmaceutically acceptable salts of the present invention can be suitably used as such or in the form of a pharmaceutical composition. These compositions (pharmaceuticals) may be solid, liquid or semi-fluid, and pharmaceutical auxiliaries and additives commonly used in the art, e.g. carriers, excipients, diluents, stabilizers, Wetting or emulsifying agents, pH- and osmotic pressure adjusting agents, flavoring or fragrances, and formulation-acceleration or excipients can be added.
[0022]
The dosage required to show a therapeutic effect can vary within a wide range, including the extent of the patient's disease being treated, symptoms and weight, and the patient's sensitivity to the active ingredient, route of administration, and number of treatments per day, etc. It can be adapted to individual conditions for each specific case, which varies depending on the case. The actual dosage of the active ingredient used can be safely determined by the attending physician in the field according to the information of the patient undergoing treatment.
[0023]
The pharmaceutical composition containing the active ingredient of the present invention usually contains 0.01 to 100 mg of the active ingredient in a unit dosage form. In certain compositions, the amount of active ingredient may naturally exceed the upper limit or lower limit described above.
[0024]
Solid pharmaceutical composition forms may be, for example, lyophilized powder ampoules which can be used for the preparation of tablets, dragees, capsules, pills, injection seats. Liquid compositions may be injections and drops, solutions, packaging solutions and drops: semi-fluid compositions may be ointments, salves, creams, mixed shakes and suppositories.
[0025]
For ease of administration, the pharmaceutical composition comprises a unit dosage form containing the amount of active ingredient administered at one time, or two, three, or one half, one third, or one quarter It is suitable to include. Such unit dosage forms are, for example, tablets, which can be divided along the groove to halve or quarterly and dispense the exact required amount of active ingredient.
[0026]
Tablets can be coated with an acid-soluble layer to ensure release of the active ingredient content after passage through the stomach. Such tablets are enteric-coated. A similar effect can be achieved by encapsulating the active ingredient.
[0027]
Pharmaceutical compositions for oral administration can contain, for example, lactose or starch as an excipient, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidine or starch paste as a binder or granulating agent. Potato starch or microcrystalline cellulose can be added as a disintegrant, but ultra amylopectin or formaldehyde casein can also be used. Talc, colloidal silicate, stearin, calcium stearate or magnesium can be used as anti-adhesive and lubricant.
[0028]
Tablets can be manufactured, for example, by tableting after wet granulation. A mixture of the active ingredient, excipients and part of the disintegrant in a given case is granulated in a suitable apparatus with an aqueous, alcoholic or hydroalcoholic solution of the binder and then the granules are dried. Other disintegrants, lubricants, anti-adhesives are added to the dried granules and the mixture is compressed into tablets. For a given tablet, the tablet is halved for ease of administration.
[0029]
Tablets may be made by tableting directly from the mixture of active ingredient and appropriate additives. In a given case, the tablet is an additive commonly used in the pharmaceutical industry, sugar, cellulose derivatives (such as methyl- or ethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, calcium phosphate, calcium carbonate, food coloring, food binder, fragrance It can be coated with an agent, a stabilizer such as an iron oxide pigment, a flavoring agent, and a coloring agent. In the case of a capsule, the capsule is filled with a mixture of active ingredients and additives.
[0030]
Liquid oral compositions can be prepared, for example, suspensions, syrups, elixirs using water, glycols, oils, alcohols, colorings and flavoring agents.
[0031]
Compositions for rectal administration are formulated into suppositories or enemas. Suppositories can contain, in addition to the active ingredient, a carrier, a so-called adeps pro suppository. Carrier is vegetable oil such as hydrogenated vegetable oil, C12-C18It may be a triglyceride of a fatty acid (preferably, a carrier of trade name Witepsol). The active ingredient is uniformly mixed with the melted depth prospository and formed into a suppository.
[0032]
A composition for parenteral administration is formulated in an injection solution. For the preparation of injectable solutions, the active ingredient is taken up in distilled water and / or various organic solvents, such as glycoethers, for example, polyoxyethylene sorbitan monolaurate or monostearate (Tween 20). , Tween 60, Tween 80) and the like. Injectables can also contain various additives, such as, for example, ethylenediaminetetraacetate, and pH adjusting and buffering agents and, in the given case, local anesthetics such as lidocaine. The injection solution containing the active ingredient of the present invention is filtered, filled into ampoules, and sterilized after filling.
[0033]
If the active ingredient is hygroscopic, it is stabilized by lyophilization.
Similar compounds structurally similar to the carboxylic acid amide derivatives of formula (I) are known in the literature.
[0034]
Substituted indol-2-yl-carbonyl-piperidine derivatives similar to the compounds of the present invention are described in Patent No. WO9618628 and two publications [J. Med. Chem., 39, 3769. (1996), and J. Med. Chem., 42, 4140. (1999)]. These compounds having a reverse transcription inhibitory effect can be used therapeutically in AIDS patients.
[0035]
Indole-2-carboxylic acid amide is also pp60C − SRCInhibiting tyrosine kinases is known [Bioorg. Med. Chem. Letters, 10, 483. (2000)] and may therefore be useful in the treatment of cancer patients. The publication does not describe NMDA receptor antagonism.
[0036]
Benzofuran-2-yl-piperidine derivatives are described in patent No. WO2000012074. These compounds have a p38-a kinase inhibitory action and can therefore be used to treat patients suffering from infections and respiratory distress syndrome with Gram-negative bacteria.
[0037]
The methanone derivatives described in Protein Sci., 6 (7), 1412. (1997) have a thrombin inhibitory action. The publication does not describe NMDA receptor antagonism.
[0038]
Surprisingly, this time, contrary to the known fact, structurally similar compounds-known to have only different enzyme inhibitory actions-novel carboxylic acid amide derivatives of formula (I) according to the invention Are excellent and prominent and selective antagonists of the NMDA (N-methyl-D-aspartate) receptor, and that many of the compounds are selective antagonists of the NRDA subtype of the NMDA receptor all right. This selectivity is important because the compound has fewer undesirable side effects.
[0039]
NMDA receptor antagonists can be used in many diseases associated with excessive secretion of glutamate, a major excitatory neurotransmitter in the central nervous system. Excessive activation of the NMDA receptor by glutamate can lead to cellular calcium oversupply. This can alter cellular function and cause a cascade of intracellular events that can even lead to neuronal death [TINS,Ten, 299-302 (1987)].
[0040]
Knowledge about the structure, function and pharmacology of NMDA receptors has been expanded by recent work in molecular biology. The NMDA receptor is a heteromeric assembly composed of at least one of at least one NR1 subunit and four NR2 subunits (NR2A-D). The two spatial distributions in pharmacological sensitivity of NMDA receptors composed of CNS and various NR2 subunits are different. Of particular interest among these is the NR2B subunit because of its restricted distribution (high density in the forebrain and spinal cord collagen). Compounds selective for this subtype are available [Curr. Pharm. Des. 5, 38-404 (1999)], stroke [Stroke 28, 2244-2251 (1997)], traumatic brain injury [Brain Res 792, 291-298 (1998)], Parkinson's disease [Exp. Neurol. 163, 239-243 (2000)], neuropathic and inflammatory pain [Neuropharmacology 38, 611-623 (1999)] Proven to be effective. NMDA receptor subtype selective antagonists are expected to show little or no nuisance side effects caused by non-selective antagonists of NMDA receptors acting in glutamate binding sites or channel pores.
[0041]
Diseases known to respond to NMDA antagonists [Drug News Perspect 11, 523-569 (1998) and WO 00/00197 international patent application] are cerebral ischemia for some reason (eg, stroke, heart surgery) Chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, human immunodeficiency virus (HIV) related nerve injury, traumatic brain or spinal cord injury, pain (e.g. Post-traumatic or post-surgical), and chronic pain symptoms such as neuropathic pain or cancer-related pain. NMDA receptor antagonists also include epilepsy, anxiety, depression, migraine, psychosis, muscle spasm, multiple infarct dementia, dementia derived from others, hypoglycemia, retinal degenerative diseases (eg, CMV retinal degenerative diseases), asthma, Can be used for tinnitus, aminoglycoside antibiotic-induced hearing loss. NMDA antagonists can be used to reduce tolerance and / or dependence on opioid treatment of pain and for example withdrawal symptoms of alcohol, opioids and cocaine.
[0042]
Since the target compound has the above biological action, the object of the present invention is also a method of treatment with a carboxylic acid amide derivative represented by the formula (I) or a salt thereof, and the mammal-human to be treated is Contains—to administer an effective amount of a compound of formula (I) of the present invention as is or as a medicament.
[0043]
During postnatal development, the neuronal NMDA receptor subunit composition is changing. Similar changes were detected in cell cultures [Eur. J. Neurosci. 10, 1704-1715 (1998)]. According to literature data and our immuno-cytochemical studies, neurons cultured in vitro for 4-7 days express mainly NR2B subunits along with NR1 subunits. Functional tests of NMDA antagonistic properties in these cells mostly reflect effects on NR2B subunit-containing receptors. Since it is known that the NMDA receptor can pass calcium ions during excitement, the activation of the NMDA receptor was measured by measuring an increase in intracellular calcium concentration after administration of an antagonist (NMDA) to the cells.
[0044]
Evaluation of in vitro NMDA antagonistic strength by measuring intracellular calcium concentration with a plate reader fluorometer
Intracellular calcium measurements were performed on primary neocortical cell cultures derived from embryos of 17-day-old Charles River rats (Johnson, MI; Bunge, RP (1992): Primary cell cultures of peripheral: central neurons and glia. In: Protocols for Neural Cell Culture, eds: Fedoroff, S .; Richardson A., The Humana Press Inc., 13-38). After separation, the cells are seeded in standard 96-well microplates and the culture is 95% air-5% CO until calcium measurement.2The temperature was maintained at 37 ° C.
[0045]
The culture was used for measurement of intracellular calcium after 4-7 days in vitro. Before the measurement, the cells are fluorescent Ca2+-A sensitive dye, Fluo-4 / AM (2-2.5 pM) was loaded. In order to stop the loading, the cells were washed twice with a measuring solution (140 mM NaCl, 5 mM KCl, 2 mM CaCl).25 mM HEPES, 5 mM HEPES-Na, 20 mM glucose, 10 μM glycine, pH = 7.4). After washing, the test compound was added to the cells in the above solution (90 μl / well). Intracellular calcium measurement was performed with a plate reader fluorometer: elevation of Fluoro-4-Fluorense, etc., intramolecular calcium was induced by the addition of 40 μM NMDA. The inhibitory strength of the test compound was assessed by measuring the decrease in calcium elevation in the presence of various concentrations of the compound. After measurement, a standard calibration curve was prepared with slight modifications, and fluorescence data was converted to calcium concentration values and used [Meth. Cell. Biol. 40, 155-181 (1994)].
[0046]
Dose-response curve and IC50-Values were calculated using data obtained from at least 3 independent experiments. Inhibition intensity at one concentration was expressed as percent inhibition of the NMDA response. S-shaped concentration-inhibition curve fits the data and IC50The value was measured as the concentration representing half of the maximum inhibition by the compound.
[0047]
The ICs of the most effective compounds measured in this test of the invention in Table 150Values are listed in the table (column 1-2), along with the most effective control compounds tested (column 3-4).
[0048]
[Table 1]
[0049]
The following are control compounds:
Co 101244: 1- [2- (4-hydroxyphenoxy) ethyl] -4-hydroxy-4- (4-methylbenzyl) piperidine
EMD 95885: 6- [3- (4-Fluorobenzyl) piperidin-1-yl] propionyl] -2,3-dihydro-benzoxazol-2-one
CP-101,606: (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol
Co-111103: 1- [2- (4-hydroxyphenoxy) ethyl] -4- (4-fluorobenzyl) piperidine
Ro 256981: R- (R*, S*) -1- (4-Hydroxyphenyl) -2-methyl-3- [4- (phenylmethyl) piperidin-1-yl] -1-propanol
[0050]
As shown in Table 1, many of the compounds of the present invention exceed the strength of the known control compounds used in the test.
[0051]
Subunit selectivity test for cells expressing recombinant rat NMDA receptor
To demonstrate the NR2B subunit selectivity of the compounds, cells transfected with rat NRla and NR2A, or NR2B subunit cDNA were used. Genes [gi508809 (rat NRla), gi205738 (rat NR2B), gi2905805 (rat NR2A)] cloned according to the sequence described in the publication are transferred to various resistance genes (hygromycin in the case of NRla or neomycin in the case of the NR2 subunit). ) Was inserted into an inducible mammalian expression vector. The constructed vector was introduced into HEK293 cells using the cationic lipid transfection method. Protein expression was induced by 3 μM muristerone A. Cells were pre-tested for 48-75 hours in the presence of 365 pM ketamine 95% air-5% CO2And maintained at 37 ° C.
[0052]
NRl a Of NMDA antagonistic strength of cells transfected with / NR2B subunit-fluorescence method
To establish cells stably expressing the NRla / NR2B receptor, transfected cells were exposed to selected antibiotics for 4 weeks to grow resistant clones. The expression of NR2B subunit protein was verified by flow cytometry based on immunocytochemistry. Positive clones were further tested for functional activity in a patch clamp experiment. The best clones producing the highest NMDA-induced ion-currents were used to test NMDA antagonism by measuring NMDA-induced increases in cytosolic calcium concentration. Induction of cellular protein expression and maintenance is similar to that described above.
[0053]
Cells were seeded in standard 96-well microplates. A plate reader-fluorescence test method was used for NMDA antagonistic measurements. This method is essentially similar to the method described above for primary culture studies of rat cortical neurons.
[0054]
NRl a Of NMDA antagonistic strength of cells transfected with / NR2A subunit-patch clamp method
Cells transiently expressing the NRla / NR2A receptor and grown on coverslips were used for patch clamp experiments. Whole-cell patch clamps were recorded by standard techniques. The cell culture is continuously extracellular fluid (140 mM NaCl, 5 mM KCl, 5 mM Hepes, 5 mM Na-Hepes, 2 mM CaCl2, 20 mM glucose, 10 μM glycine, pH 7.35). Patch pipettes with resistance between 3-6 MΩ were filled with intracellular fluid (140 mM CsCl, 11 mM EGTA, and 10 mM Hepes, pH 7.3). Internal currents induced with 100 μM NMDA were recorded from the cells with a voltage clamp of −70 mV. The compound was added using a multi-barrel syringe controlled with an electromagnetic valve. Initially, NMDA was repeatedly administered until the response was stable and then added in the presence of the test compound. The degree of inhibition—expressed as a percentage—was calculated from the highest current induced with NMDA in the presence and absence of the test compound. Selectivity rate (NR2B / NR2A) is the test dose for NR1 / 2A transfected cells and NMDA antagonistic IC for NR1 / NR2B expressing cells.50Calculated as the ratio of values.
[0055]
The result is shown in Table2.
[Table 2]
[0056]
*: Data obtained from HEK293 cells stably expressing NRla / NR2B subunits by measuring intracellular calcium concentration by plate reader fluorescence method. Average of 3 experiments.
**: Results of patch clamp experiments with transient NRla / NR2A transfected HEK cells.
Test concentrations are indicated. Averages of 3, 6, 2 experiments are shown at 4570001461, 4570002260 and CP-101,606, respectively.
Selectivity: selectivity ratio (NR2B / NR2A), test concentration in NR1 / 2A transfected cells and IC in NR1 / NR2B expressing cells50Value ratio
[0057]
According to the results of Table2, compounds 4570001461 and 4570002260 and CP-101,606 showed high selectivity for the NMDA receptor containing NR2B subunit.
[0058]
The synthesis of the compounds and pharmaceutical compositions of the present invention is illustrated by the following non-limiting examples. The compound numbers quoted in biological experiments follow the names of the compounds prepared in the examples.
[0059]
Example 1
6- [ 1- ( 4-Benzylpiperidin-1-yl ) Methanoyl ] -3H-flow [ 2 , 3- f] Benzoxazol-2-one (45 14255)
a) 3H-flow [ 2 , 3- f] Benzoxazol-2-one-6-carboxylate ethyl
Ethyl 5-hydroxy-6-aminobenzofuran-2-carboxylate [Helv. Chim. Acta 77, 100. (1994)] 0.9 g (4.2 mmol), 60 ml of tetrahydrofuran, 20% phosgene in toluene 3.1 A mixture of ml and 2.0 ml of triethylamine was stirred at room temperature for 1 h. Tetrahydrofuran was removed in vacuo, water was added to the residue and the product was extracted with ethyl acetate. The combined organic layers were washed with 5% aqueous sodium bicarbonate, water, 1N aqueous hydrochloric acid and again with water, dried over sodium sulfate and concentrated to give 1.0 g (96%) of the title compound as an oil. .
[0060]
b) 3H-flow [ 2 , 3- f] Benzoxazol-2-one-6-carboxylic acid
A mixture of 1.0 g (4 mmol) of ethyl 3H-furo [2,3-f] benzoxazol-2-one-6-carboxylate, 100 ml of ethanol and 0.5 g of potassium hydroxide was refluxed for 1 h. . The mixture was concentrated and the residue was dissolved in water and acidified with 20% aqueous sulfuric acid. The precipitated crystals were collected by filtration and washed with water to obtain 0.84 g (95%) of the title compound.
Mp .: 190-192 ° C (water)
[0061]
c) 6- [ 1- ( 4-Benzylpiperidin-1-yl ) Methanoyl ] 3H-flow [ 2 , 3- f] Benzoxazol-2-one
The title compound was prepared from 3H-furo [2,3-f] benzoxazol-2-one-6-carboxylic acid and 4-benzylpiperidine.4Was prepared according to the method described in 1.
Mp .: 123-125 ° C. (diethyl ether)
[0062]
Example 2
6- [ 1- ( 4-Benzyloxypiperidin-1-yl ) Methanoyl ] -3H-flow [ 2 , 3- f] Benzoxazol-2-one (45 14254)
The title compound was prepared from 3H-furo [2,3-f] benzoxazol-2-one-6-carboxylic acid and 4-benzyloxypiperidine.4Was prepared according to the method described in 1.
Mp .: 217-219 ° C. (diethyl ether)
[0063]
Example 3
1- ( 4-Benzylpiperidin-1-yl ) -1- ( 1 , 6-dihydro-1 , 6-Diaza as -Indasen-2-yl ) Methanon (45 14305)
a) ( Z ) -2-azido-3- ( 1-Indol-5-yl ) Methyl acrylate
In a nitrogen stream, sodium methoxide solution (prepared from 15 ml of methanol and 0.66 g (29 mmol) of sodium) was added to 1.02 g of indole-5-carbaldehyde [Helv. Chim. Acta, 1616. (1968)]. A mixture of (7 mmol), azide-methyl acetate 3.34 g (29 mmol) and methanol 7 ml was added dropwise at 0 ° C. and the resulting mixture was stirred at that temperature for 5 h. The reaction mixture was then diluted with 50 ml of water and extracted three times with 50 ml of chloroform. The combined organic layers were washed with 20 ml of water, filtered through a layer separation filter paper, and concentrated to obtain 1.3 g (77%) of the title compound.
Mp .: 130-133 ° C. (chloroform)
[0064]
b) 1 , 6-dihydro-1 , 6-Diaza as -Methyl indacene-2-carboxylate
To a boiling solution of 36 ml of xylene, 1.09 g (4.5 mmol) of methyl (Z) -2-azido-3- (1H-indol-5-yl) acrylate was added little by little. The reaction mixture is refluxed until the formation of nitrogen gas is complete, then concentrated, the residue is recrystallized with hexane, the product is filtered and washed with hexane to give 0.6 g (62%) of the title compound. It was.
Mp .: 183-184 ° C. (hexane)
[0065]
c) 1 , 6-dihydro-1 , 6-Diaza as -Indacene-2-carboxylic acid
0.53-g (2.5 mmol) methyl 1,6-dihydro-1,6-diaza-as-indacene-2-carboxylate, 0.36 g (2.5 mmol) potassium trimethylsilanolate (Aldrich) and 6.0-tetrahydrofuran The mixture of ml was refluxed for 1 h, and further 0.18 g (1.25 mmol) of potassium trimethylsilanolate was added, and after refluxing for 5 h, the reaction mixture was concentrated. The residue is mixed with 20 ml of water, the insoluble matter is collected by filtration, 0.32 ml of hydrochloric acid is added to the filtrate, the precipitated crude product is collected by filtration, and kieselgel 60 (Merck) and eluent as adsorbents. As a result, it was purified by column chromatography using chloroform: methanol = 9: 1. The product was crystallized from diethyl ether to give 0.22 g (44%) of the title compound.
Mp .: 248-250 ° C. (diethyl ether)
[0066]
d) 1- ( 4-Benzylpiperidin-1-yl ) -1- ( 1 , 6-dihydro-1 , 6-Diaza as -Indasen-2-yl ) Methanon
The title compound was prepared from 1,6-dihydro-1,6-diaza-as-indacene-2-carboxylic acid and 4-benzylpiperidine.4Was prepared according to the method described in 1.
Mp .: 186-188 ° C. (diethyl ether)
[0067]
Example 4
1- ( 4-Benzylpiperidin-1-yl ) -1- ( 6-Hydroxy-1H-indol-2-yl ) Methanon (45 13579)
6-hydroxy-indole-2-carboxylic acid [J. Chem. Soc. 1605-1608. (1948)] 5.0 g (28.2 mmol), triethylamine 4.4 ml (31.6 mmol), 4-benzylpiperidine 5.0 g (28.5 mmol) , HBTU (Advanced Chem. Tech.) 12.0 g (31.6 mmol) and dimethylformamide 50 ml were stirred at room temperature for 6 h. The precipitated product was collected by filtration and recrystallized from ethanol to give 6.75 g (71%) of the title compound. Mp: 214-215 ° C (ethanol).
[0068]
Example 5
1- [ 4- ( 4-fluorobenzyl ) Piperidin-1-yl ] -1- ( 6-Hydroxy-1H-indol-2-yl ) Methanon (45 13848)
The title compound was prepared from 4- (4-fluorobenzyl) piperidine [J. Med. Chem., 35, 4903. (1992)] and 6-hydroxy-1H-indole-2-carboxylic acid in acetonitrile at room temperature. The reaction mixture was concentrated, and the residue was purified by column chromatography using Kieselgel 60 (Merck) as an adsorbent and toluene: methanol = 4: 1 as an eluent. Mp .: 180-182 ° C (toluene).
[0069]
Example 6
1- ( 4-Benzylpiperidin-1-yl ) -1- ( 5-Nitro-1H-indol-2-yl ) Methanon (45 14205)
The title compound was prepared from 5-nitroindole-2-carboxylic acid (J. Am. Chem. Soc., 4621 (1958)) and 4-benzylpiperidine.4Was prepared according to the method described in 1. Mp .: 220-224 ° C (diethyl ether).
[0070]
Example 7
1- ( 5-Amino-1H-indol-2-yl ) -1- ( 4-Benzylpiperidin-1-yl ) Methanon (45 14244)
Mixture of 1- (4-benzylpiperidin-1-yl) -1- (5-nitro-1H-indol-2-yl) methanone 0.5 g (1.38 mmol), methanol 20 ml and 10% Pd / C catalyst 0.1 g Was hydrogenated for 5 h. The catalyst was collected by filtration, washed with methanol, and the filtrate was concentrated. The residue was treated with diethyl ether, and the precipitated product was collected by filtration. 0.27 g (59%) of the title compound was obtained. Mp .: 175-180 ° C (diethyl ether).
[0071]
Example 8
( 4-Benzylpiperidin-1-yl ) − ( 6-Hydroxy-1H-benzimidazo l -2-yl ) -Methanone (45 70001103)
a) N-butyl-N ' − ( 4-methoxy-2-nitro-phenyl ) Oxalamide
To a suspension of 44.0 g (164 mmol) of N- (4-methoxy-2-nitro-phenyl) oxalamic acid ethyl ester [J. Med. Chem., 18, 926 (1975)] and 330 ml of toluene, -16.8 ml (170 mmol) of butylamine was added at 20 ° C. The reaction mixture was stirred at room temperature for 10 h, then concentrated, the residue was crystallized with diethyl ether, the precipitated product was collected by filtration, washed with diethyl ether and dried to give 45.3 g (93.3%) of the title compound. It was. Mp .: 127-128 ° C (diethyl ether).
[0072]
b) N- ( 2-Amino-4-methoxy-phenyl ) -N ' -Butyl-oxalamide
A mixture of N-butyl-N ′-(4-methoxy-2-nitro-phenyl) oxalamide 27.0 g (91 mmol), methanol 1200 ml and 5% Pd / C catalyst 7.3 g was hydrogenated for 3 h. 600 ml of acetone was added to the reaction mixture. The catalyst was collected by filtration, washed with acetone, the filtrate was concentrated, and the residue was crystallized with diethyl ether. This gave 21.8 g (90.1%) of the title compound. Mp .: 180-181 ° C (diethyl ether).
[0073]
c) 6-methoxy-1H-benzimidazole-2-carboxylic acid Butyramide
Under a nitrogen atmosphere, 41.0 g (154 mmol) of N- (2-amino-4-methoxy-phenyl) -N′-butyl-oxalamide was stirred at 240 ° C. for 10 min. The mixture was cooled to room temperature, then 300 ml of acetone was added and stirred for 1 h. The precipitated product was collected by filtration, the filtrate was concentrated, and the residue was mixed with 150 ml of N-hexane. The precipitated product was collected by filtration, washed with hexane and dried to give 26.5 g (69.5%) of the title compound. Mp .: 125-126 ° C (N-hexane).
[0074]
d) 6-Hydroxy-1H-benzimidazole-2-carboxylic acid
6-methoxy-1H-benzimidazole-2-carboxylic acid butyramide (26.0 g, 105 mmol) and 48% hydrobromic acid aqueous solution (780 ml) were stirred at 110 ° C. for 8 hours, and then refluxed for 12 hours. The mixture was cooled to room temperature and the precipitated product was collected by filtration, washed with water until pH neutral and dried to give 14.3 g (76.2%) of the title compound. Mp .: 206-207 ° C (water).
[0075]
e) ( 4-Benzylpiperidin-1-yl ) − ( 6-Hydroxy-1H-benzimidazol-2-yl ) -Methanone (45 70001103)
6-hydroxy-1H-benzimidazole-2-carboxylic acid 3.0 g (16.75 mmol), triethylamine 2.4 ml (17.2 mmol), 4-benzyl-piperidine 3.0 g (17.1 mmol), HBTU 7.0 g (18.5 mmol) and dimethyl A mixture of 100 ml formamide was stirred at room temperature for 16 h. The reaction mixture was concentrated and the residue was purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene: methanol = 4: 1 as eluent, then recrystallized from toluene to give 3.58 g of the title compound. (63.5%) was obtained. Mp .: 186 ° C. (toluene).
[0076]
Example 9
( 6-Hydroxy-1H-benzimidazol-2-yl ) − [ 4- ( 4-methyl-benzyl ) -Piperidin-1-yl ] -Methanone (45 70001378)
6-Hydroxy-1H-benzimidazole-2-carboxylic acid [Example]8's d )] And 4- (4-methylbenzyl) piperidine [J. Org. Chem., 64, 3763 (1999)]4Was prepared according to the method described in 1. Mp .: 93 ° C. (diisopropyl ether).
[0077]
Example 10
Production of pharmaceutical composition:
a) tablet:
Active ingredient 0.01-50%, lactose 15-50%, potato starch 15-50%, polyvinylpyrrolidone 5-15%, talc 1-5%, magnesium stearate 0.01-3%, colloidal silicon dioxide 1- 3% and ultra amylopectin 2-7% were mixed, then granulated by wet granulation and tableted.
[0078]
b) Sugar-coated tablets, film-coated tablets:
The tablets produced by the above method were coated with a layer consisting of an intestine- or stomach-solubilized membrane or with sugar and talc. Dragee tablets were glazed with a mixture of beeswax and carnauba wax.
[0079]
c) capsule:
Thorough mixing of active ingredient 0.01-50%, sodium lauryl sulfate 1-5%, starch 15-50%, lactose 15-50%, colloidal silicon dioxide 1-3% and magnesium stearate 0.001-3% And the mixture was sieved and filled into hard gelatin capsules.
[0080]
d) Suspension:
Ingredients: active ingredient 0.01-15%, sodium hydroxide 0.1-2%, citric acid 0.1-3%, nipagine (sodium methyl-4-hydroxybenzoate) 0.1-3%, nipasol 0 0.005-0.02%, Carbopol (polyacrylic acid) 0.01-0.5%, 96% Ethanol 0.1-5%, Flavoring agent 0.1-1%, Sorbitol (70% aqueous solution) 20 -70% and distilled water 30-50%.
[0081]
To a solution of nipagine and citric acid in 20 ml of distilled water, carbopol was added in portions with vigorous stirring and the solution was left for 10-12 h. Subsequently, sodium hydroxide, an aqueous solution of sorbitol and finally ethanolic raspberry flavor in 1 ml of distilled water were added with stirring. Subsequently, the active ingredient was added little by little to the carrier and suspended with a throw-in homogenizer. Finally, distilled water was added to the desired final volume and the suspension syrup was passed through a colloid milling device.
[0082]
e) Suppository:
For each suppository, thoroughly mix 0.01-15% active ingredient and 1-20% lactose, then dissolve 50-95% of the adeps pro suppository (eg, Witepsol 4) The mixture of the active ingredient and lactose was mixed therein with a homogenizer, and the resulting mixture was cooled and molded.
[0083]
f) Freeze-dried powder formulation:
For injection, a 5% solution of mannitol or lactose was prepared with distilled water, and the solution was filtered to obtain a sterile solution. A solution of 0.01-5% active ingredient was also prepared with distilled water for injection, and this solution was filtered to obtain a sterile solution. These two solutions were mixed aseptically and filled into ampoules 1 ml at a time, the contents of the ampule were lyophilized, and the ampule was sealed in a nitrogen stream. Prior to administration, the contents of the ampoule are dissolved in sterile water or 0.9% (physiological) sterile aqueous sodium chloride solution.
Claims (7)
R1、R2、R3およびR4のうちの1つは−OHまたは−NH2基であって、他は水素原子であるか、あるいは、
隣接する2つのR1、R2、R3およびR4基は適宜、1つまたはそれ以上の同一または異なる更なるヘテロ原子、並びに−CO−基、−CH=基および/または−CH2−基と共に、5〜6員のホモ−またはヘテロ−環を形成して、R1、R2、R3およびR4基の他の2つは水素原子であり;
R5およびR6はそれらの間の窒素原子と共に、飽和または不飽和の4〜6員のヘテロ環を形成し、上記ヘテロ環は適宜、ヒドロキシ基、フェニル、フェノキシ、フェニル−(C1−C4アルキル)、フェニル−(C1−C4アルコキシ)、フェノキシ−(C1−C4アルキル)、アニリノ、フェニル−(C1−C4アルキルアミノ)、[フェニル−(C1−C4アルキル)]−アミノ、ベンゾイル、ヒドロキシ−ジフェニルメチル、C1−C4アルコキシカルボニル−フェノキシメチルまたはベンズヒドリデン基(ここで、これらは場合により、芳香族環上で1またはそれ以上のハロゲン原子、シアノ基、ヒドロキシ基、C1−C4アルキル基、またはC1−C4アルコキシ基で置換される)で置換され;
Yは窒素原子または=CH−であり、
Xは−NH−または−CH2−基であり、あるいは隣接するR1〜R4基が適宜、1つまたはそれ以上の同一または異なる更なるヘテロ原子、−CO−基、−CH=基、および/または−CH2−基と共に5〜6員のホモ−またはヘテロ−環を形成する場合には、Xは酸素原子であり得る]
で示されるカルボン酸アミド誘導体、または酸もしくは塩基と共に形成するそれらの医薬的に許容され得る塩、並びに医薬に通常用いられる担体、充填剤を含有する、疼痛の処置および緩解のための医薬組成物。Biologically effective amount of formula (I) as active ingredient:
One of R 1 , R 2 , R 3 and R 4 is an —OH or —NH 2 group and the other is a hydrogen atom, or
Two adjacent R 1 , R 2 , R 3 and R 4 groups are optionally substituted with one or more of the same or different further heteroatoms, as well as a —CO— group, —CH═ group and / or —CH 2 —. Together with the group forms a 5-6 membered homo- or hetero-ring, the other two of the R 1 , R 2 , R 3 and R 4 groups are hydrogen atoms;
R 5 and R 6 together with the nitrogen atom between them form a saturated or unsaturated 4- to 6-membered heterocycle, which is optionally substituted with a hydroxy group, phenyl, phenoxy, phenyl- (C 1 -C 4 alkyl), phenyl- (C 1 -C 4 alkoxy), phenoxy- (C 1 -C 4 alkyl), anilino, phenyl- (C 1 -C 4 alkylamino), [phenyl- (C 1 -C 4 alkyl) )]-Amino, benzoyl, hydroxy-diphenylmethyl, C 1 -C 4 alkoxycarbonyl-phenoxymethyl or benzhydridene groups, where these are optionally one or more halogen atoms, cyano groups, hydroxy group, optionally substituted with C 1 -C 4 alkyl groups or substituted with C 1 -C 4 alkoxy group,);
Y is a nitrogen atom or = CH-,
X is -NH- or -CH 2 - is a group or adjacent R 1 to R 4 groups are suitably one or more identical or different additional hetero atom, -CO- group, -CH = group, X may be an oxygen atom when forming a 5- to 6-membered homo- or hetero-ring with and / or the —CH 2 — group]
Or a pharmaceutically acceptable salt thereof formed with an acid or a base, and a pharmaceutical composition for treating and relieving pain, comprising a carrier or filler normally used in medicine. .
で示される、請求項1記載の医薬組成物。The carboxylic acid amide derivative of formula (I) is represented by formula (Ia):
The pharmaceutical composition of Claim 1 shown by these.
1−(4−ベンジルオキシピペリジン−1−イル)−1−(6−ヒドロキシ−1H−インドール−2−イル)メタノン、
1−(4−ベンジルピペリジン−1−イル)−1−(4−ヒドロキシ−1H−インドール−2−イル)メタノン、
1−(4−ベンジルピペリジン−1−イル)−1−(6−ヒドロキシ−1H−インドール−2−イル)メタノン、
1−(4−ベンジルピペリジン−1−イル)−1−(5−ヒドロキシ−1H−インドール−2−イル)メタノン、
1−(6−ヒドロキシ−1H−インドール−2−イル)−1−[4−(4−メチルベンジルオキシ)ピペリジン−1−イル)]メタノン、
1−(6−ヒドロキシ−1H−インドール−2−イル)−1−(4−フェノキシメチルピペリジン−1−イル)メタノン、
1−(6−ヒドロキシ−1H−インドール−2−イル)−1−[4−(4−メチルベンジル)−4−ヒドロキシピペリジン−1−イル)]メタノン、
1−[4−(4−フルオロベンジルピペリジン−1−イル)]−1−(6−ヒドロキシ−1H−インドール−2−イル)メタノン、
1−(6−ヒドロキシ−1H−インドール−2−イル)−1−(4−フェノキシピペリジン−1−イル)メタノン、
1−[4−(4−フルオロベンジルピペリジン−1−イル)]−1−(5−ヒドロキシ−1H−インドール−2−イル)メタノン、
1−(4−ヒドロキシ−1H−インドール−2−イル)−1−(4−フェノキシメチルピペリジン−1−イル)メタノン、
1−(6−ヒドロキシ−1H−インドール−2−イル)−1−(4−フェノキシ−3,6−ジヒドロ−2H−ピリジン−1−イル)メタノン、
1−(4−ベンジルオキシピロリジン−1−イル)−1−(6−ヒドロキシ−1H−インドール−2−イル)メタノン、
1−[4−(4−クロロベンジルオキシ)−ピペリジン−1−イル)]−1−(6−ヒドロキシ−1H−インドール−2−イル)メタノン、
(4−ベンジルピペリジン−1−イル)−(6−ヒドロキシ−1H−ベンゾイミダゾール−2−イル)メタノン、および
(6−ヒドロキシ−1H−ベンゾイミダゾール−2−イル)−[4−(4−メチルベンジル)ピペリジン−1−イル]メタノン
からなる群から選ばれる、請求項1記載の医薬組成物。The carboxylic acid amide derivatives of formula (I) are:
1- (4-benzyloxypiperidin-1-yl) -1- (6-hydroxy-1H-indol-2-yl) methanone,
1- (4-benzylpiperidin-1-yl) -1- (4-hydroxy-1H-indol-2-yl) methanone,
1- (4-benzylpiperidin-1-yl) -1- (6-hydroxy-1H-indol-2-yl) methanone,
1- (4-benzylpiperidin-1-yl) -1- (5-hydroxy-1H-indol-2-yl) methanone,
1- (6-hydroxy-1H-indol-2-yl) -1- [4- (4-methylbenzyloxy) piperidin-1-yl)] methanone,
1- (6-hydroxy-1H-indol-2-yl) -1- (4-phenoxymethylpiperidin-1-yl) methanone,
1- (6-hydroxy-1H-indol-2-yl) -1- [4- (4-methylbenzyl) -4-hydroxypiperidin-1-yl)] methanone,
1- [4- (4-fluorobenzylpiperidin-1-yl)]-1- (6-hydroxy-1H-indol-2-yl) methanone,
1- (6-hydroxy-1H-indol-2-yl) -1- (4-phenoxypiperidin-1-yl) methanone,
1- [4- (4-fluorobenzylpiperidin-1-yl)]-1- (5-hydroxy-1H-indol-2-yl) methanone,
1- (4-hydroxy-1H-indol-2-yl) -1- (4-phenoxymethylpiperidin-1-yl) methanone,
1- (6-hydroxy-1H-indol-2-yl) -1- (4-phenoxy-3,6-dihydro-2H-pyridin-1-yl) methanone,
1- (4-benzyloxypyrrolidin-1-yl) -1- (6-hydroxy-1H-indol-2-yl) methanone,
1- [4- (4-chlorobenzyloxy) -piperidin-1-yl)]-1- (6-hydroxy-1H-indol-2-yl) methanone,
(4-benzylpiperidin-1-yl)-(6-hydroxy-1H-benzimidazol-2-yl) methanone, and
The pharmaceutical composition according to claim 1, selected from the group consisting of (6-hydroxy-1H-benzimidazol-2-yl)-[4- (4-methylbenzyl) piperidin-1-yl] methanone.
で示されるカルボン酸アミド誘導体、および酸または塩基と共に形成するそれらの医薬的に許容され得る塩は、
式(II):
で示されるカルボン酸と、式(III):
で示されるアミンとの間にアミド結合を形成させ;
次いで適宜、得られた式(I)[式中、R1、R2、R3、R4、R5、R6、XおよびYは、請求項1の定義と同じである]で示されるカルボン酸アミド誘導体を、公知の方法による、新規な置換基の導入および/または既存の置換基の変更もしくは除去、および/または塩の形成および/または塩からの化合物の遊離によって、式(I)で示される別の化合物に変換する、ことによって得られる、請求項1記載の医薬組成物。Formula (I):
And the pharmaceutically acceptable salts thereof formed with acids or bases are:
Formula (II):
A carboxylic acid represented by formula (III):
An amide bond is formed with the amine represented by
And then optionally obtained formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and Y are as defined in claim 1. Carboxylic acid amide derivatives may be converted to formula (I) by known methods by introducing new substituents and / or modifying or removing existing substituents and / or forming salts and / or releasing compounds from salts. The pharmaceutical composition of Claim 1 obtained by converting into another compound shown by these .
で示されるカルボン酸アミド誘導体および/または酸もしくは塩基と共に形成するその医薬的に許容され得る塩と、医薬に通常用いられる担体、充填剤とを混合することを特徴とする、該方法。A method for producing a pharmaceutical composition according to claim 1, comprising the formula (I):
And a pharmaceutically acceptable salt formed with an acid or base, and a carrier or filler commonly used in medicines, and the method.
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HU0004123A HU227197B1 (en) | 2000-10-24 | 2000-10-24 | Nmda receptor antagonist carboxylic acid amide derivatives and pharmaceutical compositions containing them |
PCT/HU2001/000099 WO2002034718A1 (en) | 2000-10-24 | 2001-10-15 | Amide derivatives as nmda receptor antagonists |
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Families Citing this family (54)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL204456B1 (en) * | 2001-02-20 | 2010-01-29 | Chugai Pharmaceutical Co Ltd | Azoles as malonyl-coa decarboxylase inhibitors useful as metabolic modulators |
US7709510B2 (en) * | 2001-02-20 | 2010-05-04 | Chugai Seiyaku Kabushiki Kaisha | Azoles as malonyl-CoA decarboxylase inhibitors useful as metabolic modulators |
CA2461603A1 (en) * | 2001-09-24 | 2003-04-03 | Elan Pharmaceuticals, Inc. | Substituted amines for the treatment of neurological disorders |
ATE372335T1 (en) * | 2002-02-01 | 2007-09-15 | Novo Nordisk As | AMIDES OF AMINOALKYL-SUBSTITUTED AZETIDINES, PYRROLIDINES, PIPERIDINES AND AZEPANES |
US7101898B2 (en) | 2002-02-01 | 2006-09-05 | Novo Nordisk A/S | Amides of aminoalkyl-substituted azetidines, pyrrolidines, piperidines and azepanes |
GB0205165D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
GB0205162D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
GB0205170D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
GB0205176D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
GB0205166D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
GB0205175D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
US20050215614A1 (en) * | 2002-10-15 | 2005-09-29 | Rigel Pharmaceuticals, Inc. | Substituted indoles and their use as hcv inhibitors |
EP1565453A4 (en) * | 2002-11-22 | 2007-10-10 | Merck & Co Inc | 2- (4-benzyl)-1-piperidinyl)methyl|benzimidazole-5-ol derivatives as nr2b receptor antagonists |
US7732162B2 (en) | 2003-05-05 | 2010-06-08 | Probiodrug Ag | Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases |
EP1653944B1 (en) * | 2003-08-01 | 2010-11-10 | Chugai Seiyaku Kabushiki Kaisha | Heterocyclic compounds useful as malonyl-coa decarboxylase inhibitors |
EP1658071B1 (en) * | 2003-08-01 | 2008-09-10 | Chugai Seiyaku Kabushiki Kaisha | Cyanoguanidine-based azole compounds useful as malonyl-coa decarboxylase inhibitors |
JP4648317B2 (en) * | 2003-08-01 | 2011-03-09 | 中外製薬株式会社 | Piperidine compounds useful as malonyl-CoA decarboxylase inhibitors |
CA2567801C (en) | 2004-05-28 | 2013-12-03 | Unigen Pharmaceuticals, Inc. | Diarylalkanes as potent inhibitors of binuclear enzymes |
PL1761519T3 (en) * | 2004-06-21 | 2008-09-30 | Hoffmann La Roche | Indole derivatives as histamine receptor antagonists |
HU227119B1 (en) * | 2004-07-29 | 2010-07-28 | Richter Gedeon Nyrt | Indole and benzimidazole carboxylic acid amide derivatives and pharmaceutical compositions containing them |
HUP0401523A3 (en) * | 2004-07-29 | 2007-05-02 | Richter Gedeon Vegyeszet | Indole-2-carboxamide derivatives, pharmaceutical compositions containing them and process for producing them |
CN101087618A (en) * | 2004-12-23 | 2007-12-12 | 航行药物公司 | Leuprolide acetate and acetylcholinesterase inhibitors or NMDA receptor antagonists for the treatment of alzheimer's disease |
WO2007022268A2 (en) * | 2005-08-16 | 2007-02-22 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
WO2007063839A1 (en) * | 2005-11-30 | 2007-06-07 | Shionogi & Co., Ltd. | Cyclohexane derivative |
EP2520567A3 (en) | 2006-02-23 | 2012-12-12 | Shionogi & Co., Ltd. | Nitrogen-containing heterocycle derivatives substituted with cyclic group |
WO2008023258A1 (en) * | 2006-08-23 | 2008-02-28 | Pfizer Products Inc. | Piperidine derivatives |
JP5379692B2 (en) | 2006-11-09 | 2013-12-25 | プロビオドルグ エージー | 3-Hydroxy-1,5-dihydro-pyrrol-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcers, cancer and other diseases |
EP2091944B1 (en) | 2006-11-17 | 2011-05-18 | Pfizer Inc. | Substituted bicyclocarboxyamide compounds |
JP5523107B2 (en) | 2006-11-30 | 2014-06-18 | プロビオドルグ エージー | Novel inhibitors of glutaminyl cyclase |
AU2007328993B2 (en) | 2006-12-08 | 2012-05-10 | F. Hoffmann-La Roche Ag | Indoles |
EP2079694B1 (en) | 2006-12-28 | 2017-03-01 | Rigel Pharmaceuticals, Inc. | N-substituted-heterocycloalkyloxybenzamide compounds and methods of use |
EA200901140A1 (en) | 2007-03-01 | 2010-04-30 | Пробиодруг Аг | NEW USE OF GLUTAMINYL CYCLLASE INHIBITORS |
DK2142514T3 (en) | 2007-04-18 | 2015-03-23 | Probiodrug Ag | Thiourea derivatives as glutaminyl cyclase inhibitors |
NZ584049A (en) | 2007-09-21 | 2011-05-27 | Sanofi Aventis | (carboxylalkylene-phenyl)-phenyl-oxalamides, method for the production thereof, and use of same as a medicament |
ES2740974T3 (en) | 2008-07-21 | 2020-02-07 | Unigen Inc | Series of compounds for whitening (lightening) the skin |
EA022007B1 (en) | 2009-09-11 | 2015-10-30 | Пробиодруг Аг | Heterocylcic derivatives as inhibitors of glutaminyl cyclase |
JP5851998B2 (en) * | 2009-10-27 | 2016-02-03 | バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングBayer Intellectual Property GmbH | Haloalkyl-substituted amides as insecticides and acaricides |
US9051296B2 (en) | 2009-11-16 | 2015-06-09 | Raqualia Pharma Inc. | Aryl carboxamide derivatives as TTX-S blockers |
JP6026284B2 (en) | 2010-03-03 | 2016-11-16 | プロビオドルグ エージー | Inhibitors of glutaminyl cyclase |
US8269019B2 (en) | 2010-03-10 | 2012-09-18 | Probiodrug Ag | Inhibitors |
EP2560953B1 (en) | 2010-04-21 | 2016-01-06 | Probiodrug AG | Inhibitors of glutaminyl cyclase |
ES2570167T3 (en) | 2011-03-16 | 2016-05-17 | Probiodrug Ag | Benzimidazole derivatives as glutaminyl cyclase inhibitors |
CN109896935A (en) | 2011-03-24 | 2019-06-18 | 尤尼根公司 | It is used to prepare the Compounds and methods for of diarylpropane |
US9387212B2 (en) | 2012-04-20 | 2016-07-12 | Ucb Biopharma Sprl | Methods for treating Parkinson's disease |
CN104603106B (en) * | 2012-09-07 | 2017-05-10 | 诺华股份有限公司 | Indole carboxamide derivatives and uses thereof |
KR101551313B1 (en) * | 2014-07-28 | 2015-09-09 | 충남대학교산학협력단 | Novel indene derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating blindness related diseases containing the same as an active ingredient |
MX2017002775A (en) | 2014-09-15 | 2017-08-10 | Rugen Holdings (Cayman) Ltd | Pyrrolopyrimidine derivatives as nr2b nmda receptor antagonists. |
US10662183B2 (en) | 2014-11-07 | 2020-05-26 | The Regents Of The University Of Michigan | Inhibitors of myocardin-related transcription factor and serum response factor (MRTF/SRF)-mediated gene transcription and methods for use of the same |
AU2016270677B2 (en) | 2015-06-01 | 2020-11-12 | Rugen Holdings (Cayman) Limited | 3,3-difluoropiperidine carbamate heterocyclic compounds as NR2B NMDA receptor antagonists |
WO2017155890A1 (en) * | 2016-03-11 | 2017-09-14 | Ohio State Innovation Foundation | Novel small molecule antimicrobials |
US11000526B2 (en) | 2016-11-22 | 2021-05-11 | Rugen Holdings (Cayman) Limited | Treatment of autism spectrum disorders, obsessive-compulsive disorder and anxiety disorders |
WO2018119374A1 (en) | 2016-12-22 | 2018-06-28 | Cadent Therapeutics | Nmda receptor modulators and uses thereof |
ES2812698T3 (en) | 2017-09-29 | 2021-03-18 | Probiodrug Ag | Glutaminyl cyclase inhibitors |
WO2020196828A1 (en) * | 2019-03-28 | 2020-10-01 | 武田薬品工業株式会社 | Nitrogen-containing heterocyclic compound |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5965073A (en) * | 1982-10-05 | 1984-04-13 | Kowa Co | Indole derivative |
US5354758A (en) * | 1992-12-16 | 1994-10-11 | Japan Tobacco Inc. | Benzomorphans useful as NMDA receptor antagonists |
TW406075B (en) | 1994-12-13 | 2000-09-21 | Upjohn Co | Alkyl substituted piperidinyl and piperazinyl anti-AIDS compounds |
ATE309215T1 (en) * | 1996-09-30 | 2005-11-15 | Aventis Pharma Inc | NMDA (N-METHYL-D-ASPARTATE) ANTAGONISTS |
PE20000728A1 (en) | 1998-06-26 | 2000-08-21 | Cocensys Inc | HETEROCYCLES 4-BENZYL PIPERIDINE ALKYLSULFOXIDE AND THEIR USE AS SUBTYPE-SELECTIVE NMDA RECEPTOR ANTAGONISTS |
EP1107758A2 (en) | 1998-08-28 | 2001-06-20 | Scios Inc. | Use of piperidines and/or piperazines as inhibitors of p38-alpha kinase |
BR0007532A (en) * | 1999-01-13 | 2001-11-20 | Univ New York State Res Found | Methods to identify protein kinase inhibitors, to test compounds for a capacity to inhibit protein kinase activity and to inhibit a protein kinase, non-peptide protein tyrosine kinase inhibitor, and, method of treating a condition responsive to a protein kinase inhibitor in a patient |
US6476041B1 (en) * | 1999-10-29 | 2002-11-05 | Merck & Co., Inc. | 1,4 substituted piperidinyl NMDA/NR2B antagonists |
-
2000
- 2000-10-24 HU HU0004123A patent/HU227197B1/en unknown
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- 2001-10-15 EP EP01978687A patent/EP1328514A1/en not_active Withdrawn
- 2001-10-15 RU RU2003115490/04A patent/RU2271361C2/en not_active IP Right Cessation
- 2001-10-15 UA UA2003054619A patent/UA74850C2/en unknown
- 2001-10-15 AU AU2002210782A patent/AU2002210782A1/en not_active Abandoned
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2003
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2004
- 2004-12-28 US US11/024,637 patent/US7361670B2/en not_active Expired - Fee Related
- 2004-12-28 US US11/024,638 patent/US7365083B2/en not_active Expired - Fee Related
- 2004-12-29 US US11/025,288 patent/US7378431B2/en not_active Expired - Fee Related
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Also Published As
Publication number | Publication date |
---|---|
EP1328514A1 (en) | 2003-07-23 |
HUP0004123A2 (en) | 2002-10-28 |
HU0004123D0 (en) | 2000-12-28 |
US20050113359A1 (en) | 2005-05-26 |
US7365083B2 (en) | 2008-04-29 |
US7378431B2 (en) | 2008-05-27 |
US7375116B2 (en) | 2008-05-20 |
US20050113360A1 (en) | 2005-05-26 |
US6919355B2 (en) | 2005-07-19 |
RU2271361C2 (en) | 2006-03-10 |
JP2004512324A (en) | 2004-04-22 |
HU227197B1 (en) | 2010-10-28 |
US20030199552A1 (en) | 2003-10-23 |
US20050159451A1 (en) | 2005-07-21 |
PL365377A1 (en) | 2005-01-10 |
HUP0004123A3 (en) | 2003-03-28 |
AU2002210782A1 (en) | 2002-05-06 |
US20050113361A1 (en) | 2005-05-26 |
WO2002034718A1 (en) | 2002-05-02 |
US7361670B2 (en) | 2008-04-22 |
UA74850C2 (en) | 2006-02-15 |
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